SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Using the rabbit ear as an experimental model, a composite flap based on an anastomosed central artery and vein can be created and its viability determined. This inexpensive model can be used to train plastic surgical residents in microsurgery and in further investigations of the microcirculation of flaps and their survival.
Experimental animal models have made it possible to study some of the biological, biochemical, and pharmacological parameters involved in the use of radiolabeled monoclonal antibody for therapy and detection. Although such models are less appropriate for studies of dosimetry and the host's immune response to the monoclonal antibody, some general principles have been derived from the various model systems that have largely held true in studies in patients. Some of the points learned from experimental animal models will be illustrated in this paper.
Sheep were used as an experimental model to study trypanosomiasis. Twelve animals were infected with Trypanosoma brucei brucei, and the clinical evolution of the disease in the sheep corresponded closely to that described in human patients. The main clinical signs of the experimental infection were hyperthermia, anaemia, loss of weight and behavioural disturbances. Death occurred in all cases after a mean time of 75 days. Trypanosomes were detected in blood films nine to 15 days after inoculation, and the parasitaemia was usually mild and irregular. Changes in the cerebrospinal fluid--increase in leucocyte counts and the presence of trypanosomes--appeared after about 45 days. This model would provide a valuable way of testing the effectiveness of new therapeutic drugs.
PURPOSE: The most common complication of cataract surgery is the development of posterior capsule opacification (PCO). Hyperplasia of the lens epithelium is one of the main cellular events following phacoemulsification and was found to be an important feature contributing to opacification of the posterior capsule. We investigated the feasibility of killing the residual lens epithelial cells by retroviral-mediated transfer of the herpes simplex virus-thymidine kinase (HSV-tk) gene, a well-studied suicide gene, into rabbit lens epithelial cells followed by ganciclovir (GCV) treatment. METHODS: The capacity of retroviral vectors to transfer genes into rabbit lens epithelial cells was determined either in vitro (culture of rabbit lens epithelial cells) or in vivo (experimental model of PCO in rabbits) using cDNA encoding the beta-galactosidase (LacZ) reporter gene. To evaluate the efficiency of suicide gene therapy (infection with retroviral vectors encoding the HSV-tk gene followed by GCV treatment) we determined the sensitivity of HSV-tk infected lens epithelial cells to different concentrations of GCV in vitro. Then, in an experimental model of PCO, rabbits were treated with HSV-tk retroviral vectors at the end of the surgery and they received repeated intracameral and intravitreal injections of GCV at the concentration determined by the in vitro experiments. RESULTS: Infection efficiency using LacZ retroviral vectors was about 29% in vitro and 10% in vivo. After infection of the HSV-tk cDNA in vitro, the cell killing effect of GCV was evaluated. A significant enhancement (four- to five-fold) of the cell sensitivity to GCV was shown in FLY-DFGtk as compared with mock infected (P < 0.01) cells even without selection of the HSV-tk positive cells. The GCV concentration leading to 50% reduction in cell number (IC50) was 50 microg/ml. In vivo infection with a HSV-tk vector led to the tk gene transfer into lens epithelial cells. Despite this local HSV-tk gene expression, we could not prevent capsule opacification. CONCLUSIONS: Lens epithelial cells were successfully infected both in vitro and in vivo by beta-galactosidase and HSV-tk genes via retroviral vectors. In vitro infected lens epithelial cells displayed a strong sensitivity to GCV treatment. In vivo, we could not prevent capsule opacification in the rabbit model, very likely due to the limited level of the HSV-tk gene expression. However, our results suggest that virus-mediated suicide gene therapy might be a feasible treatment strategy to prevent capsule opacification with a more powerful vector.
BACKGROUND: Most of the published animal studies that have evaluated tumor growth and port site metastases in laparoscopy have utilized a cell suspension model and thus cannot be compared to the clinical situation. Although solid tumor models have been developed, there has been no experimental model that establishes an orthotopic tumor in the rectum, reflecting the clinical situation of a solid colonic cancer. METHODS: Tumor cells (colon adenocarcinoma DHD/K1/TRb) were administered intraperitoneally in rats, which were used as solid tumor donors. A 20-mg piece of solid tumor from the donor was placed in a submucosal blister created in the rectum wall of the study rats. The approach to the submucosal blister was made through the mucosa after contralateral enterotomy. In order to validate the model, this intervention was performed in 10 cases (group A). After 10 days of intervention, the rats were submitted to resection of the rectum and histological examination of the specimen. In another 10 rats (group B), manipulation of the tumor was performed after 10 days to cause tumor cell spillage. The likelihood of tumor dissemination was investigated in this group 20 days after this intervention. RESULTS: Group A developed solid tumors in seven of 10 cases (70%). All of the tumors were localized between the muscular and the mucosal layer, with preservation of the serosa and without affecting the enterotomy. In all of the rats in group B, macroscopic tumor was observed in the upper rectum (100%) 10 days after its induction. Twenty days after tumor manipulation, nine rats had local tumor dissemination; two of them also had general tumor dissemination in the abdominal cavity. CONCLUSIONS: We established a novel solid colonic tumor model in rats for the investigation of intraoperative tumor cell spillage during resection of the colon and the development of port site metastases.
The pathogenesis of scleroderma is still elusive, although autoimmune mechanism involvement has been suggested. The present study was designed to investigate whether or not rat scleroderma would appear as one of the symptoms in a recently described model for autoimmune disease. The model is based on manipulation or reconstitution of the immune system after lethal irradiation and syngeneic bone marrow transplantation by temporary administration of the immunosuppressive drug cyclosporine-A. Withdrawal of cyclosporine-A 6-12 wk after bone marrow transplantation gives rise to autoimmune reactions causing clinical pathology similar to graft-versus-host disease. We discuss the chronic phase of this disease, approximately 30 wk after cyclosporine-A was withheld at that time-about one-third of the rats had developed histologic skin lesions comparable to those seen in patients with scleroderma. Therefore, we propose this model as a new, experimental autoimmune model for scleroderma in humans.
We attempted to develop an experimental model of chronic inflammatory pain in mice. The mice were injected intradermally at the base of the tail with various kinds of irritants (yeast, carrageenin, mustard and adjuvant). The pain threshold was measured by the pressure method every 60 min for 5 hr and once a day at the same time throughout the experimental period. The group of 10% yeast-injected mice exhibited the most intensive hyperalgesia. The analgesic effect of various types of analgesic drugs were studied, comparing the effects in normal mice and various kinds of irritants-induced hyperalgesia mice. It was demonstrated by observing ED50 values that nonsteroidal antiinflammatory drugs (NSAIDs), narcotic analgesic drugs and agonist/antagonist type of analgesic drugs were effective, but CNS-acting drugs were ineffective in yeast hyperalgesia mice. In comparison with yeast hyperalgesia mice, larger doses of analgesic drugs were required in normal mice and other irritants-treated mice. Especially, acidic NSAIDs were more effective in yeast hyperalgesia mice than normal mice. It was suggested that acidic NSAIDs specifically inhibit inflammatory pain. Moreover, yeast hyperalgesia mice are useful for the quantitative measurement of analgesic drugs.
On the experimental model of denervation-reinnervation syndrome of mouse shank muscles neurotrophic effects of jashaltinsky medicinal mud were studied. In experimental mice therapeutic mud has been applied on the small back, tail and rib areas of the body 10 days after nerve crushing. On day 11 after nerve crushing a stable reproduction of a compound nerve action potential with constant amplitude was revealed in repetitive (50 Hz) nerve stimulation.
We investigated the need for continuous immunosuppression to maintain experimental tumours derived from human uveal melanoma cells implanted in the choroid of pigmented rabbits. Two groups of pigmented rabbits immunosuppressed with cyclosporin A (CsA) were implanted with human uveal melanoma cells in the suprachoroidal space. After 5 weeks, CsA was discontinued in group 2. Animals were treated with prophylactic antibiotics and examined weekly for tumour growth, weight and secondary effects; blood urea nitrogen levels were measured every two weeks. Autopsies and histopathological studies were performed after death or euthanasia at the end of week 12. The difference between the groups in the development of ophthalmoscopic tumours was not statistically significant 5 weeks after implantation. Tumours in group 1 grew progressively throughout the experiment, whereas group 2 tumours showed marked regression 3-4 weeks after discontinuing CsA. Tumours in group 1 were significantly larger and had greater mitotic activity and showed more ciliary body, optic nerve and extrascleral invasion than tumours in group 2, which showed massive fibrosis, minimal mitotic activity and marked inflammatory cell infiltration. Continuous immunosuppression with CsA seems to be necessary to maintain tumour growth in this experimental model of uveal melanoma.
A new experimental rabbit model of acute purulent osteomyelitis is proposed. The model is reproduced by percutaneous introduction of 4 million St. aureus microorganisms into the medullary channel of the femoral bone after aseptic destruction of the bone marrow by ethyl alcohol and hot saline. The model satisfies the demands of good reproduction, reduces probability of contamination of periosteal tissues during intraosteal inoculation and provides reproduction of local inflammation without its generalization which results in reduced number of fatal outcomes among experimental animals.
A new experimental model for the production of early stages of invasive intestinal amebiasis in hamsters or guinea pigs with axenic or monoxenic cultures of Entamoeba histolytica of the HM1:IMSS strain is reported. The model is called the washed-closed cecal loop, because it involves the washing out of the cecum contents of conventionally raised animals and the formation of a closed loop, into which amebas are inoculated. Colonization occurred in all inoculated animals. After 48 hr, macroscopic ulcerations of the cecal mucosa were found in approximately one-half (5/12) of the animals inoculated with axenic amebas and in more than two-thirds (10/12) of those inoculated with monoxenic parasites. The amebic nature of the mucosal ulcerations was confirmed by light and transmission electron microscopy, as well as by scanning electron microscopy (SEM) of fractured samples of cecal mucosa. SEM provided a rapid and reliable technique to assess both the extent and the nature of the lesions. This model is particularly useful for the study of the pathogenesis of early intestinal lesions produced by virulent amebas, and may also be applied to experimental studies on the immunology of invasive intestinal amebiasis.
Effects of various emetic and antiemetic drugs were studied using Suncus murinus for its potential use as an experimental model in emetic research. Subcutaneous injection of nicotine bitartrate (10-15 mg/kg), veratrine sulfate (0.5-1.0 mg/kg), emetine dihydrochloride (40-80 mg/kg) and oral administration of copper sulfate (20-100 mg/kg) caused dose-dependent emesis in suncus. The ED50 of nicotine, veratrine, emetine and copper sulfate were 7.9, 0.4, 47.6 and 21.4 mg/kg, respectively. However, subcutaneously injected apomorphine hydrochloride (0.1-100 mg/kg), digitoxin (0.5-1.0 mg/kg) and orally administered emetine dihydrochloride (10-80 mg/kg) did not induce the vomiting. Chlorpromazine and promethazine decreased the emetic effect of nicotine, veratrine and copper sulfate, but scopolamine hydrobromide was not effective. These results indicate that the Suncus murinus is sensitive to various emetic and antiemetic drugs and can be used as a new experimental animal model for the emesis. Emetic behavior of suncus was discussed in comparison with other animals.
From a review of renal development and experimental cystic disease, the following observations can be made: 1. The previous theories developed to explain cystic renal disease (nonunion, failure of regression, and obstruction to urine flow) do not adequately fit with the numerous recent observations made in studies of most experimental models or in human renal cystic disease. 2. The most acceptable theory to date for most types of renal cystic abnormalities (except those due to known obstruction of urine flow) is that abnormalities of the tubular supporting wall occur, probably as a result of toxic or metabolic injury to the tubular cells of the wall and the related interstitial tissues, which are exposed to the highest concentrations of these compounds. This theory would also help explain the etiology of cystic renal diseases in man and should lead to attempts to isolate toxic factors or enzyme abnormalities in susceptible families and in early cases. 3. Induction of cystic abnormalities through a variety of experimental manipulations and drugs reveals impressive strain, sex, and species variability, and these differences should be more carefully examined. 4. The same chemical that induces a cystic change in the mature, fully developed kidney may cause changes which are quite different (location, severity, etc.) in both the fetal and newborn kidney, in which continual nephrogenesis is occurring. 5. Many of the previous explanations of cystic changes require careful reinterpretation of the findings (to reconcile certain differences), and confirmatory studies should be performed to help piece together some of the puzzling observations noted, such as the cystic changes seen with adrenocorticosteroids, and their relationship to potassium depletion.
Little consistency has been manifest among investigators in choosing an appropriate experimental model for maxillofacial bone research. In an effort to develop a protocol for the experimental analysis of maxillofacial nonunions, previous studies using calvarial and mandibular defects as models were reviewed. The creation of nonunions in animals within the calvaria and mandible was size dependent. Defects of a size that will not heal during the lifetime of the animal may be termed critical size defects (CSDs). A rationale was postulated for testing bone repair materials (BRMs) using CSDs in a hierarchy of animal models. This rationale suggests that testing should be initiated in the calvaria of the rat and rabbit, followed by testing in the mandibles of dogs and monkeys. While calvarial CSDs have been established in the rat, rabbit, and dog, further research is necessary to determine the CSD in the calvaria of the monkey, as well as the mandibles of dogs and monkeys.
There are no experimental models which mimic the most common causes of human acute pancreatitis, i.e. gallstones and alcohol abuse. However, existing models can reproduce the morphology and physiological derangements of certain phases of the illness. Current models have been useful in elucidating the earliest events involved in the initiation and progression of pancreatitis. However, very few animal studies demonstrate effective therapeutic intervention when treatment is given after the induction of experimental pancreatitis. Since immediate intervention is unachievable in human disease, most experimental therapies have not been successfully applied to clinical disease.
Hepatic fibrosis is characterized by abnormal collagen deposition resulting from increased collagen synthesis and decreased collagen degradation. Cytochrome P450 mediates major drug metabolizing enzyme activity in the liver and this activity is reduced in hepatic fibrosis. In this study we assess cytochrome P450 and CYP 1A mRNA in livers of animals that have been induced to hepatic fibrosis using the heterologous serum induced model of fibrosis in rats compared to controls. Fibrosis was confirmed by assessing the collagen in liver sections as quantified by Sirius red/Fast green staining, a quantitative measure of fibrosis as well as by visualization of the hepatic fibrosis. Collagen levels in the liver sections of heterologous serum induced fibrotic rats was increased by 33% compared to controls and a typical fibrotic pattern was seen. Messenger RNA was prepared from heterologous serum induced fibrotic rats and compared to controls. CYP 1A2 was assessed using a specific probe and the CYP 1A2 level was significantly reduced in the heterologous serum induced fibrotic rats compared to controls. These results further suggest that cytochrome P450 is reduced in the presence of hepatic fibrosis. Thus, in three well established experimental models of hepatic fibrosis which had clearly developed hepatic fibrosis (as shown by Sirius red/Fast green staining), cytochrome P450 mediated enzyme activity, or specifically, CYP 1A messenger RNA is decreased. We then investigated a transgenic mouse, deficient in the arylhydrocarbon hydroxylase receptor (AHR), which has undetectable levels of CYP 1A messenger RNA. We quantitated the collagen in liver sections obtained from AHR knockout mice compared to controls, as an indication of the presence of hepatic fibrosis. Collagen concentration was significantly increased by 53% (P<0.0005) in sections from Ahr-/- (knockout) mice compared to wild-type controls. Collagen in livers of the Ahr+/- heterozygous mice was not different from wild-type controls. The increase in collagen concentration in liver sections is an indication of fibrosis in Ahr-/- mice. Collagen protein deposition was also elevated in liver sections from bile duct ligated rats (by 44%) compared to sham operated controls, was elevated in liver sections from heterologous serum induced fibrosis in rats (33%) compared to controls, and was elevated in liver sections from yellow phosphorous induced hepatic fibrosis (74%) compared to vehicle treated controls. In conclusion, these results indicate that cytochrome P450 and specific subtypes of P450, the CYP 1A subgroup, are significantly reduced in three experimental models of hepatic fibrosis when there is evidence of increased collagen deposition in the livers. These results also indicate that mice that are deficient in CYP 1A have elevated levels of hepatic collagen protein, an indication of hepatic fibrosis.
PURPOSE: To examine experimentally the feasibility of transfemoral endoluminal repair of aneurysms containing the ostia of essential branch arteries. METHODS: In a canine model (n = 4), suprarenal aortic aneurysms were created by suturing an artificial patch onto an anterior arteriotomy. Following a 2-week recovery period, the dogs underwent endovascular exclusion of their aneurysms using an aortic stent-graft with separate renal artery branch grafts. Outcome was evaluated using angiography, intravascular ultrasound (IVUS), Doppler flow, invasive pressure monitoring, and autopsy, respectively. RESULTS: Successful creation and subsequent endovascular exclusion of the aneurysm using aortic stent-grafts and separate bilateral renal artery stent-grafts was achieved in all trials. Angiographically, all aneurysms were excluded from aortic flow and all renal arteries were patent at completion of the procedure. With IVUS, good graft apposition and absence of perigraft flow were demonstrated in all animals. Mean pressure in the aneurysmal sac at completion of the procedure was 40 +/- 7 mmHg, compared to a mean systemic blood pressure of 105 +/- 8 mmHg (p < 0.05). At autopsy, no gross intimal damage was seen in the aorta or the renal arteries, and intact aortic grafts and branch grafts without twisting, coiling, or kinking were found in all trials. CONCLUSIONS: In an acute animal model, suprarenal aortic aneurysms can be excluded from the circulation with preservation of renal flow using an endoluminally placed aortic stent-graft with separate branch grafts.
The aim of the present thesis was to develop, refine, and assess experimental models for the study of proliferative vitreo-retinal disorders. An intravitreal injection of a colloidal solution of microparticles was used in the primate eye to produce pathologic changes including intraocular cell invasion, cell proliferation, neovascularization, collagen synthesis, and tractional retinal detachment. In a separate primate model for laser-induced subretinal neovascularization, the origin and the occurrence of macrophages was evaluated. Examinations were performed using ophthalmoscopy, slit-lamp microscopy, light microscopy, and transmission electron microscopy. Cell cultures were employed to study the effects of vitreous humor and macrophages on the proliferation of cultured retinal pigment epithelial (RPE) cells and cultured fibroblasts using a Coulter counter. Morphologic changes were documented by phase micrography. A quantitative estimation of the extracellular matrix deposition of fibrous proteins by macrophage-modulated RPE cells as well as by vitreous-modulated RPE cells was done using enzymatic digestion and radioactive labeling techniques. A qualitative analysis of the types of collagen that was deposited in the extracellular matrices by vitreous modulated cultures was also made using indirect immunofluorescence. Using a newly developed RPE cell specific monoclonal antibody, the avidin-biotin-peroxidase labeling technique was finally employed to test the phenotypic epitope expression of macrophage-modulated and non-modulated RPE cells. A new experimental in vivo model for pathologic changes that characterize proliferative vitreo-retinal disorders was developed in the primate eye. In the model for laser-induced subretinal neovascularization, macrophages were shown to be principally recruited from the systemic circulation. Using cell cultures, it was found that both macrophage-conditioned medium and vitreous humor, separately or combined, exert mitogenic effects on RPE cells and fibroblasts. The combined effect of the two stimuli was additive, but not synergistic, on both cell lines. When incubated with macrophage-conditioned culture medium or vitreous humor, RPE cells exhibited a metaplastic transformation towards fusiform, spindle-shaped cells that were morphologically indistinguishable from fibroblasts. The extracellular matrices of RPE cells modulated by macrophage-conditioned medium also appeared converted to a more striated pattern as compared to non-modulated controls. The metaplastic transformation of cultured RPE cells reverted when experimental stimuli, macrophage-conditioned medium or vitreous humor, were withdrawn. A new in vitro method for evaluating fibrous protein deposition in the extracellular matrix by RPE cells was also described. RPE cells, that were modulated by macrophage-conditioned medium or vitreous humor, deposited less fibrous proteins per cell.(ABSTRACT TRUNCATED AT 400 WORDS)