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Disruption of the intestinal barrier and bacterial translocation in an experimental model of intestinal obstruction.

Clinical evidence and the use of experimental models in laboratory animals indicate that the intestine is a reservoir of microorganisms that can cause systemic infection in the human. The purpose of this work was to study the possible effect of intestinal obstruction (IO) on the mechanical and chemical barriers that bring protection against microorganisms crossing from the intestinal lumen towards the systemic tissues. We demonstrated that 24 hours after IO, histological and ultrastructural alterations do occur, seriously compromising the structure of the intestinal barrier in 100% of the studied animals. Likewise, it was observed that during the same period, microorganisms translocation from intestine to the peritoneal cavity and liver (100 and 80% respectively) occurred. The lungs were spared. Changes observed in the intestinal epithelium are related to a process similar to that produced by intestinal ischemia: mitochondrial destruction, with subsequent decrease of its capacity to supply energy and to preserve the equilibrium and structure of the intestinal epithelium. We propose that translocation of enteric bacteria may be the cause of the infection that brings about the death a significant group of animals at 48 hours (27%) and 72 hours (33%) post-IO.

Animals↗

Comparison of experimental models for Streptococcus suis infection of conventional pigs.

Four different experimental models for Streptococcus suis-induced disease were compared to find a model that closely mimics naturally occurring disease in conventional pigs. Fourteen, 2-week old pigs free of S. suis type 2 were used in 2 experiments. In experiment 1, 3 pigs were inoculated intravenously (IV) and 3 pigs intranasally (IN) with S. suis. Two out of 3 of the IV-inoculated pigs exhibited signs of severe central nervous system disease (CNS) and were euthanized. Streptococcus suis type 2 was isolated from whole blood, joints, and serosal surfaces of both pigs. No clinical signs and no growth of S. suis were detected in the IN-inoculated pigs. In experiment 2, 4 pigs were inoculated IV and another 4 were inoculated IN with the same isolate as in experiment 1. One hour before inoculation the IN-inoculated pigs were given 5 mL of 1% acetic acid intranasally (IN-AA). All the IV-inoculated pigs showed CNS disease and lameness, and 2 of the pigs became severely affected and were euthanized. All the IN-AA inoculated pigs exhibited roughened hair coats and 2 pigs developed severe CNS disease and were euthanized. Streptococcus suis was isolated from the joints and blood of 3 pigs in the IV-inoculated group. Streptococcus suis was isolated from blood of 2 pigs, meninges of 3 pigs, and joints of 1 pig in the IN-AA inoculated group. Natural exposure to S. suis most likely occurs by the intranasal route. The IN-AA model should serve as a good model for S. suis-induced disease, because the natural route of exposure is intranasal and the IN-AA model was effective in inducing disease that mimics what is observed in the field.

Administration, Intranasal↗

An experimental model of acute immune-complex uveitis.

We developed an experimental model of anterior uveitis by injecting ovalbumin or bovine serum albumin into the anterior chamber of sensitized rabbits. All the eyes showed leakage of serum proteins into the aqueous humor within 30 min. and developed uveitis within 24 hrs. which lasted at least a week. On histological examination, large numbers of polymorphonuclear (PMN) leucocytes and only occasional mononuclear cells were seen in the iris, the ciliary body and the irido-corneal angle. Immunohistological examination revealed 7s gamma globulin in the walls of blood vessels, in the interstitium and inside the PMN leucocytes. Contact radiographs of eyes challenged repeatedly showed extensive neovascularization of the iris and ciliary body.

Animals↗

The effects of acetyl-l-carnitine on experimental models of learning and memory deficits in the old rat.

Experimental models of learning and memory deficits in aged rats can be studied by means of behavioural tests that provide an important tool for evaluating the effect of drugs on these parameters. Active and passive avoidance tests showed a clear impairment of learning and memory capacity of old rats. These tests were also used to study the behavioural effect of acetyl-l-carnitine in aged rats. The subchronic treatment with this drug was followed by a significant improvement of acquisition and retention of avoidance responses, indicating a facilitation of learning and memory capacity of aged rats.

Acetylcarnitine↗

[An experimental model for testing the emotional interactions of animals].

A new experimental model has been worked out for testing of animals emotional interaction; it represents a maze, consisting of two start chambers, passages and central chambers. Individual testing of animals behaviour was carried out on the basis of recording of active preventing of electrocutaneous stimulation of another animal, which was realized in the maze by means of choice by the tested animals of one of two possible movement directions excluding electrocutaneous stimulation of the animal-victim in the central chamber. The experiments were carried out on 35 male Wistar rats. As a result the animals were divided into three groups according to their behaviour type--per cent of running delivering the rat-victim from the electric current. The elaborated model has revealed a high precision of typification at testing of the individual behaviour in conditions of rats emotional interaction and it may be used for individual behavioural tests of other small laboratory animals.

Animals↗

[Experimental model with the additional source of endogenous serotonin].

The only experimental approach to the increase in the body serotonin level is a pharmacological one that has a number of shortcomings. The authors suggest an experimental model with additional source of endogenous serotonin (ASS-model) which occurs after embryonal gastrointestinal tract transplantation beneath the skin of adult syngeneic mice. The developing transplants showed significant amounts of serotonin and serotonin-producing enterochromaffin cells. The ASS-model provides long-term and selective increase in the blood serotonin content (by 40% on the average) with no changes being detected in the brain. This model may be used for studies on the role of serotonin in peripheral regulation of the physiological systems.

Animals↗

Bile-induced DNA strand breaks and biochemical analysis of bile acids in an experimental model of anomalous arrangement of the pancreaticobiliary ducts.

A canine experimental model for the anomalous arrangement of the pancreaticobiliary ducts (APBD) was made to investigate the effects of bile acids on carcinogenesis. Seven adult mongrel dogs underwent dorsal pancreatico-cholecystostomy to serve as a functional model for APBD, and six dogs underwent the same procedure with the pancreatic duct ligated as a control group. Bile from the gallbladder was taken 14 months after surgery for bile acid analysis by HPLC. DNA strand breaks in HeLa cells induced by the bile were also investigated in situ by nick translation method. As a result, the fraction of cholic acid tended to be lower, and that of deoxycholic acid slightly higher in APBD-dogs (N.S.). The ursodeoxycholic acid percentage in APBD-dogs significantly decreased compared with that in the control and normal dogs (p < 0.05). Extremely high frequency of DNA strand breaks was shown in only two out of seven APBD-dogs. In those two dogs, the cholic acid percentage decreased and that of deoxycholic acid increased extremely. These findings suggest that the alteration of the bile composition in APBD caused frequent DNA strand breaks and repair which might lead to gene mutation and biliary tract carcinoma.

Animals↗

Effects of simvastatin administration in an experimental model of cancer cachexia.

OBJECTIVE: We evaluated whether statins, in view of their anti-inflammatory properties, may effectively prevent the onset or modulate the severity of muscle wasting during cancer cachexia. METHODS: Simvastatin was administered to rats bearing the Yoshida AH-130 ascites hepatoma, a well-studied cytokine-dependent experimental model of cancer cachexia. RESULTS: Quite surprisingly, the drug negatively affected the wasting pattern induced by the AH-130 hepatoma. In fact, the administration of simvastatin to tumor hosts induced a further weight reduction of all the tissues examined except for the soleus, in the absence of significant effects of simvastatin on tumor growth or on food intake. No effects were observed after simvastatin administration in control animals, with the exception of a significant (P < 0.05) reduction in heart weight. CONCLUSIONS: Simvastatin administration, although capable of negatively modulating the inflammatory response, did not prevent muscle wasting in this experimental model of cancer cachexia. Moreover, the further muscle loss observed in simvastatin-treated tumor-bearing animals suggests that a note of caution should be introduced in treating cancer patients with statins in view of the possible occurrence of harmful side effects.

Animals↗

A review of the action of tacrolimus (FK506) on experimental models of rheumatoid arthritis.

Tacrolimus (FK506) is an immunosuppressive drug, widely used for organ transplantation and atopic dermatitis. Tacrolimus exerts its immunosuppressive effects primarily by interfering with the activation of T cells, via inhibition of calcineurin. Recent clinical studies have also demonstrated the efficacy of tacrolimus in the treatment of rheumatoid arthritis (RA), an autoimmune disease in which T cells play a pivotal role in pathogenesis. Inflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-6 are involved in development of the disease. Recently, modes of action of tacrolimus on RA have been intensively studied in in vitro and animal arthritis models, demonstrating that tacrolimus exerts various novel actions as an anti-rheumatic drug. The pharmacological action of tacrolimus suggests that it has potential to specifically suppress the production of pathogenic inflammatory cytokines with a low frequency of infection, improve joint inflammation and bone/cartilage destruction, fully recover loss of functional status, exert rapid relief in arthritic pain, and promote osteogenic and chondrogenic differentiation. Here we review the action of tacrolimus on experimental models of RA, with a focus on our recent studies, and provide further insight into experimental models used for identifying efficacious anti-rheumatic drugs.

Analgesics↗

The rat-tail artery maintained in culture: an experimental model.

The rat-tail artery was maintained in vitro for 2 weeks to investigate its suitability as an experimental model. The criteria were that (a) it should retain the overall histological organization with normal ultrastructural appearance of the smooth-muscle cells; (b) stored neurotransmitter which could be activated by experimental treatment should be absent; and (c) smooth-muscle ion transport mechanisms should fall within normal range. Vessels were maintained in Falcon tissue-culture dishes in Dulbecco's modified Eagle's medium. Either 2% or no serum supplement was found to be more suitable than 10% serum due to the high rate of cell proliferation induced by the latter. Light and electron microscopy of cross sections of the vessels indicated that the overall normal vessel architecture was retained, and the ultrastructural features predicted normal function. There were no discernible differences dependent on the length (up to 8- to 10-cm lengths) of the cultured vessel. Preliminary experiments with fluorescent microscopy showed that stored neurotransmitter in the nerves of the vessel wall was no longer present after 48 hr. Ultrastructural examination revealed that storage vesicles in vitro lost their dense cores, representing noradrenalin, between 41 and 48 hr in culture. Normal ion transport mechanisms were retained in the smooth-muscle cells of the arteries in vitro for up to 2 weeks when tested with ion-specific electrodes. Morphological and physiological evidence support the suitability of the rat-tail artery as a model for experimental testing of vascular tissues.

Animals↗

Development and evaluation of an experimental model of cutaneous columnaris disease in koi Cyprinus carpio.

A reproducible, experimental model of columnaris disease was developed to study the pathogenesis of cutaneous disease associated with Flavobacterium columnare infection in koi (Cyprinus carpio). In experimental infections, lesions were usually restricted to skin and fins; gill necrosis was not a consistent finding. Cytologic and histopathologic examinations provided a presumptive diagnosis of columnaris disease. Specific detection of F. columnare was done using the polymerase chain reaction and DNA in situ hybridization (ISH). Polymerase chain reaction allowed the detection of F. columnare in fresh biological material and in formalin-fixed, paraffin-embedded tissues. The DNA ISH technique allowed the identification and localization of F. columnare in formalin-fixed, paraffin-embedded tissues. Using these molecular techniques, F. columnare was readily detected in skin specimens from infected fish; however, the bacterium was infrequently detected in specimens of liver, kidney, and spleen. These observations suggest that columnaris disease generally presents as a cutaneous disease that is unassociated with systemic infection in koi. Hematologic studies indicated that most infected koi developed microcytic, normochromic, nonregenerative anemia and leukopenia characterized by lymphopenia, mild neutrophilia, and monocytosis. Biochemical changes in diseased fish included significant hyperglycemia, hyponatremia, and hypochloridemia.

Animals↗

Efficacy of antimicrobial agent treatment in relation to treatment regimen: experimental models and clinical evaluation.

The effect of the duration of treatment on clinical and bacteriological efficacy is generally poorly evaluated for antimicrobial agents. Infection model studies have to a large extent concentrated on endocarditis. In clinical trials systematic and well controlled studies are abundant in the field of urinary tract infections and streptococcal tonsillopharyngitis, but almost non-existent in other types of infections. Paradoxically, most of the infections studied by experimental models are uncommon in man and evaluation of optimal treatment periods for these by clinical trial is therefore difficult. In the evaluation of new antimicrobial agents, closer collaboration of experimental model and clinical trial investigators is required to design models of infections and clinical trials to evaluate optimal duration of treatment.

Animals↗

[Application of methods for hemodynamic monitoring in critical cardiac pathology (an experimental model for assessment of hemodynamics)].

Hemodynamic assessment of critically compromised patients with cardiac pathology is one of the goals of recent diagnostics and treatment strategies. Different methods for assessment of hemodynamics are applied in clinical practice. However, applied methods (invasive and noninvasive) have specific advantages and disadvantages. These are discussed in the article. First experience of experimental model for assessment of hemodynamics in laboratory conditions is analyzed in the article. In the year 2002 it was explored a possibility to use standard procedure to evaluate hemodynamics for laboratory animals in Kaunas University of Medicine. It were selected 6 laboratory animals of different weight and sex. 7 measurements of hemodynamics were performed. Standard methodics was successfully applied in the experimental model. Results, method limitations and recommendations for further studies are presented in the article.

Animals↗

To-and-for extracorporeal lung assist (ECLA) through a single catheter-in premature goats as an experimental model of infant respiratory Insufficiency.

A new to-and-fro V-V bypass extracorporeal lung assist (ECLA) through a single catheter as a blood access was investigated for its efficacy on six premature goats delivered by Cesarean section at a gestational age of 118 approximately 139 days as an experimental model of infant respiratory insufficiency, then applied to a human premature infant suffering from life threatening barotrauma that had developed from mechanical pulmonary ventilation. The extracorporeal bypass flow and the gas flow to the artificial membrane lung were controlled to keep Pa(O)(2) above 40 mmHg and Pa(CO)(2) within normal limits. The neonate's own lungs were treated with a continuous positive airway pressure of 5 approximately 12 cmH(2)O, apneic oxygenation or IMV. Two goats weighing 1250 g and 700 g died 2 approximately 2.5 hours after birth from severe circulatory distress. However, the other four neonates which were heavier than 2000 g, were successfully weaned from ECLA, and three of these could be weaned from mechanical ventilation as well. A human infant also survived and was weaned from ECLA on the third day.(Tanoue T, Terasaki H, Sadanaga M et al.: To-and-fro extracorporeal lung assist (ECLA) through a single catheter-in premature goats as an experimental model of infant respiratory insufficiency.

Journal Article↗

[Development of an experimental model for spontaneous lymph node metastasis of human esophageal carcinoma in nude mice--histopathological analysis].

Three human squamous cell carcinoma cell lines (HPL-EsC-1-K, -S, and -M) originated from a male patient with esophageal carcinoma were established and were studied on their tumorigenic and metastatic properties in nude mice. All cell lines grew in the hind foot pads following subcutaneous inoculation and produced popliteal lymph node metastasis dose (2-8 x 10(6)/mouse)-dependently. Based on the histopathological findings on serial sections of the lymph nodes, the stages of lymph node invasion by cancer cells were classified into 4 stages (St. 0-III). The time course of lymph node metastasis of EsC-K cells were examined. Advanced stage of metastasis increased according to the time elapsed after tumor cell inoculation. Incidence of metastasis of EsC-K cells were not affected by host factors such as sex differences, anti-asialo GM1 antibody treatment on the hosts. Today, there are few experimental models for studies on spontaneous lymph node metastasis of human carcinomas. This experimental model provides a useful research tool for studies on the biology and therapy for lymph node metastasis of esophageal cancer.

Animals↗

Acute renal failure. II. Experimental models of acute renal failure: imperfect but indispensable.

Acute renal failure (ARF) due to ischemic or toxic renal injury, a clinical syndrome traditionally referred to as acute tubular necrosis (ATN), is a common disease with a high overall mortality of approximately 50%. Little progress has been made since the advent of dialysis more than 30 years ago in improving this outcome. During this same period, a considerable amount of basic research has been devoted to elucidating the pathophysiology of ATN. The ultimate goal of this research is to facilitate the development of therapeutic interventions that either prevent ARF, ameliorate the severity of tubular injury following an acute ischemic or toxic renal insult, or accelerate the recovery of established ATN. This research endeavor has been highly successful in elucidating many vascular and tubular abnormalities that are likely to be involved in ischemic and toxic ARF. This information has led to impressive advances in the development of a number of different pharmacological interventions that are highly effective in ameliorating the renal dysfunction in animal models of ARF. Although these developments are exciting and promising, enthusiasm of investigators involved in this endeavor has been tempered somewhat by the results of a few recent clinical studies of patients with ATN. These trials, designed to examine the efficacy in humans of some of the interventions effective in animal models of ARF, have resulted in little or no benefit. This is therefore an important time to reevaluate the approaches we have taken over the past three to four decades to develop new and effective treatments for ATN in humans. The major goals of this review are 1) to evaluate the relevance and utility of the experimental models currently available to study ischemic and toxic renal injury, 2) to suggest novel experimental approaches and models that have the potential to provide advantages over methods currently available, 3) to discuss ways of integrating results obtained from different experimental models of acute renal injury and of evaluating the relevance of these findings to ATN in humans, and 4) to discuss the difficulties inherent in clinical studies of ATN and to suggest how studies should be best designed to overcome these problems.

Acute Kidney Injury↗

Anti-inflammatory effects of jojoba liquid wax in experimental models.

Jojoba [Simmondsia chinensis (Link 1822) Schneider 1907] is an arid perennial shrub grown in several American and African countries. Jojoba seeds, which are rich in liquid wax, were used in folk medicine for diverse ailments. In the current study, the potential anti-inflammatory activity of jojoba liquid wax (JLW) was evaluated in a number of experimental models. Results showed that JLW caused reduction of carrageenin-induced rat paw oedema in addition to diminishing prostaglandin E2 (PGE2) level in the inflammatory exudates. In a test for anti-inflammatory potential utilizing the chick's embryo chroioallantoic membrane (CAM), JLW also caused significant lowering of granulation tissue formation. Topical application of JLW reduced ear oedema induced by croton oil in rats. In the same animal model, JLW also reduced neutrophil infiltration, as indicated by decreased myeloperoxidase (MPO) activity. In addition, JLW ameliorated histopathological changes affected by croton oil application. In the lipopolysaccharide (LPS)-induced inflammation in air pouch in rats, JLW reduced nitric oxide (NO) level and tumor necrosis factor-alpha (TNF-alpha) release. In conclusion, this study demonstrates the effectiveness of JLW in combating inflammation in several experimental models. Further investigations are needed to identify the active constituents responsible for the anti-inflammatory property of JLW.

Animals↗

Insights into mechanisms of antiarrhythmic drug action from experimental models of atrial fibrillation.

Atrial fibrillation (AF) remains a challenge to medical therapy. Over the past several years, a variety of experimental models of AF have been developed. These have provided insights into mechanisms underlying AF and antiarrhythmic drug action against the arrhythmia. A variety of drugs effective against clinical AF, including flecainide, propafenone, procainamide, and sotalol, have been found to terminate experimental AF. All of these agents appear to act by prolonging the wavelength for atrial reentry at rapid rates, thereby increasing the size and decreasing the number of functional circuits maintaining the arrhythmia. While the ability to terminate AF is determined by refractoriness prolongation at rapid rates, refractoriness prolongation at slow rates (e.g., sinus rhythm) can prevent AF induction by premature beats. Thus, drugs with strong reverse use-dependence (like sotalol) may be much more effective in preventing than in terminating AF. Spacial heterogeneity in refractoriness is an important contributor to AF occurrence in some models, particularly vagal AF, and is reduced by some (but not all) drugs that terminate AF. New insights are being gained into mechanisms of electrical remodeling, which promotes AF maintenance when rapid atrial rates are maintained, such as during AF. This electrical remodeling may be an interesting novel target for therapy of AF. Insights into AF mechanisms obtained in experimental models of AF should help in the development of new and improved therapeutic approaches.

Animals↗