Radical correction of single ventricle in experimental model: experimental and clinical results.
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Notes on the early history of infective endocarditis and the development of an experimental model.
Experimental models of infective endocarditis antedate Garrison and Freedman's work in 1970. The hypothesis of the role of parasites (microorganisms) microscopically observed in vegetations and cardiac valves of patients with endocarditis was first put forth by Winge in Sweden in 1869. Winge's work led Klebs and Rosenbach in Germany to establish, between 1878 and 1881, an animal model of experimental endocarditis in which the aortic valves of rabbits were perforated with a metallic probe (loaded with septic material) introduced through the carotid artery. Ten years after Winge's work, Pasteur emphasized the importance of bacteriologic "blood cultures." During the period 1881-1886, Netter and Grancher (Pasteur's associates) introduced a method for drawing aseptic blood samples from patients with clinical endocarditis and performing bacteriologic blood cultures. In Vienna in 1885-1886, Orth, Weichselbaum, and Wyssokowitsch further developed Rosenbach's procedure of inducing experimental endocarditis by injecting material from a bacterial culture into a rabbit's ear vein. The development of an experimental model of endocarditis by investigators in the latter part of the nineteenth century provided anatomopathological and bacteriologic data that in turn led to a better understanding of infective endocarditis.
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New therapies for optic neuropathies: development in experimental models.
Experimental models of human diseases have affected the design and direction of both basic and clinical research into understanding the pathogenesis and treatments of demyelinating disease, stroke, and hereditary disorders of the central nervous system. However, in spite of major advances in molecular research that have linked Leber Hereditary Optic Neuropathy to mutations in mitochondrial DNA, there has been relatively little focus in applying basic scientific methodologies to optic neuropathies other than glaucoma. The relative absence of detailed scientific knowledge about the basic mechanisms involved in the pathogenesis of optic nerve injury has contributed to the use of empiric therapies for neuro-ophthalmic optic neuropathies. Over the past decade major clinical trials, such as the Optic Neuritis Treatment Trial and Ischemic Optic Neuropathy Decompression Trial, have proven that currently available treatment options for demyelinating and ischemic optic neuropathies are ineffective and can even be harmful. Although the pathogenesis of visual failure in demyelinating, ischemic, and hereditary optic neuropathies appears diverse, a final common pathway for irreparable optic nerve injury may exist. This article reviews several models of experimental optic neuropathies that may aid in the development of novel treatments for neuro-ophthalmic disorders of the optic nerve during the 21st century.
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Tumor-based rhythms of anticancer efficacy in experimental models.
Experimental tumor models constitute a prerequisite toward chronotherapy testing in cancer patients. Studies in experimental models are required to understand the relation between tumor rhythms and antitumor treatments efficacy. In healthy tissues, cell proliferation, and differentiation processes are regulated precisely and exhibit marked circadian rhythmicity. Experimental and human tumors can retain circadian rhythms or display altered oscillations. Healthy tissues can also display rhythm modifications, possibly related to cancer stage. Cellular rhythms modulate the metabolism of cytotoxic agents and the cellular response to them; hence, they determine the chronopharmacology of anticancer drugs. Circadian rhythms in host tolerability and/or cancer chemotherapy efficacy have been demonstrated with nontoxic doses of drugs in several experimental tumor models, while in other ones a circadian-time effect was only seen within a specific dose range. The usual coupling between tolerability and efficacy rhythms of anticancer agents has resulted in significant improvement of their therapeutic index. Results of laboratory animal studies have been extrapolated to the design of clinical cancer therapy trials involving a chronobiological approach.
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[Meningeal gliomatosis: development of experimental models].
Experimental models of meningeal gliomatosis (MG) have been produced by intracisternal inoculation of C6 glioma and 9L glioma cells into Wistar and Fisher 344 rats, respectively. The tumor growth was steady and fast in both MG models if 10(6) cells were implanted. Median survival time(MST) of rats inoculated with tumor cells was inversely related to the number of cells inoculated. The clinicopathological features observed in both MG models were similar to those seen in diffuse leptomeningeal involvement of gliomas in human beings. The models will be useful for investigating the pathophysiology of meningeal gliomatosis and the efficacy of chemotherapeutic agents.
Animals↗
Deep venous thrombosis in the baboon: an experimental model.
Experimental models of deep venous thrombosis, heretofore, have not been available for laboratory studies. This investigation establishes a novel model of venous thrombosis by inhibiting the protein C system combined with venous stasis and subtle venous injury. Ten adolescent baboons were studied in pairs, with one animal receiving saline solution (B2, B4, B6, B8, B10) and one being exposed to thrombogenic reagents (B1, B3, B5, B7, B9). These reagents represented a combination of a monoclonal antibody (HPC4) to protein C, 1 to 4 mg/kg administered over 5 minutes, and tumor necrosis factor administered over 3 minutes at a dose of 150 micrograms/kg through a catheter placed into the left superficial femoral vein with distal ligation. To encourage stasis, a pediatric size blood pressure cuff was inflated to 40 mm Hg on the right thigh for 50 minutes of every hour during the first experimental day (day 1) in B5 to B10. The animals were observed for a 6-hour period on day 1 and then for an 11- to 15-day period until sacrifice. Hemodynamic and hematologic parameters were recorded along with duplex imaging of the iliac veins and inferior vena cava on a daily basis. Venography was performed on day 1, day 4, and the day of sacrifice. At sacrifice the entire iliac and vena caval system was carefully dissected, opened, and photographed. Experimental animals given the HPC4 and tumor necrosis factor developed left iliac vein thrombosis extending into the inferior vena cava. Duplex imaging, venography, and autopsy revealed that control animals receiving saline solution never developed comparable thrombus. Experimental subjects exhibited thrombus on duplex imaging by day 4 (B1), day 3 (B3), day 2 (B5), 120 minutes (B7), and 360 minutes (B9) after receiving HPC4 and tumor necrosis factor. Venograms performed on day 1 exhibited thrombus in B5, B7, and B9. The extent of thrombus, the timing of its occurrence, and its effect on the animals' left leg followed a dose-dependent relationship for the animals in which the occlusive blood pressure cuff was used. Significantly greater declines in blood pressure, white blood cell count, and platelet count were found in affected animals given HPC4 and tumor necrosis factor reagents as compared to control subjects. All affected animals demonstrated the appearance of fibrin split products and a markedly prolonged prothrombin time. This investigation, for the first time, establishes a reproducible model of deep venous thrombosis involving inhibition of protein C that will facilitate further laboratory studies on venous thrombosis.
Animals↗
Fatty acids and colon cancer in experimental models.
Experimental models have several advantages in the study of colon cancer. They can be used to tightly control diet, examine putative intermediate markers, test hypotheses about mechanisms of carcinogenesis, and quantify development of tumors in a short time. Dietary issues that have been studied in animal models but are unresolved include the concept of the effects of total fat compared with energy intake, composition of the basal diet, linoleic acid requirements, and interactions of fat with other nutrients. Intermediate markers that have been probed in animal or in vitro studies include cytokinetics, aberrant crypt foci, eicosanoids and hydroxyoctadecadienoic acids, ornithine decarboxylase, tyrosine kinase, protein kinase C, and gene expression. Colon cancer is studied in animals primarily with use of chemicals that are relatively specific inducers of these tumors, but transplantable models and transgenic animals are also used. Total dietary fat is generally thought to affect colon tumorigenesis, but there does not appear to be any specific fatty acid that promotes the development of colon cancer. Several studies indicate that n-3 fatty acids from marine sources alter a variety of biological intermediates and inhibit colonic tumorigenesis; this is probably mediated via the eicosanoid pathway. Although there are undoubtedly multiple cellular changes elicited by certain fatty acids, our current knowledge of this area suggests that specific fatty acid metabolites or their targets are the likely mediators in this sequence.
Animals↗
Congenital bilateral coronal suture synostosis in a rabbit and craniofacial growth comparisons with experimental models.
Experimental rabbit models of postnatal coronal suture (CS) synostosis have helped make significant contributions towards the understanding and surgical management of human congenital craniosynostosis. The present study compares craniofacial growth patterns in animals with experimental CS immobilization and in a rabbit born in our laboratory with congenital CS synostosis. The study sample consisted of 10 sham controls, 14 experimental animals with bilateral CS immobilization, and one animal with congenital, bilateral CS synostosis. At 1.5 weeks of age, all animals had amalgam markers placed on either side of the frontonasal, coronal, and anterior lambdoid sutures. At this time, the experimental animals had bilateral CS immobilization using methyl-methacrylate. Serial lateral head x-rays were taken at 1.5, 6, 12, and 18 weeks of age. Results revealed that by 1.5 weeks of age the congenital animal already exhibited changes in the cranial vault, cranial base, midface, and orthocephalic cranial base angles compared to controls. By 6 weeks of age, animals with experimental immobilization showed compensatory growth patterns similar to the congenital animal, particularly at the calvarial sutures and upper midface. This pattern continued through 18 weeks. Results showed that experimental, postnatal CS immobilization produced similar craniofacial growth patterns to those observed for our single congenital animal, but to a lesser degree, and therefore validates, in part, findings from experimental rabbit models of synostosis.
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Arterial and muscle oxygen tension in experimental models of asthma. Experimental models of asthma.
The immediate-type airway response in anesthetized dogs and rhesus monkeys to two antigens (ascaris and keyhole limpet hemocyanin) and pharmacologic agents (histamine, methacholine and prostaglandin F2alpha) were studied. The pulmonary function abnormalities demonstrated by changes in breathing frequency, peak expiratory flow rate, pulmonary resistance, expiratory-inspiratory time ratio, tidal volume, and dynamic compliance were compared with simultaneous determinations of arterial pO2, muscle pO2 or both, using indwelling electrodes. The results demonstrate that the O2 determinations provide an additional parameter of study of these experimental models of asthma, and that it may be one of the more sensitive indicators of an induced airway response of the immediate-type. The hypoxia parallels the degree of severity of the respiratory response and demonstrates a further similarity of this model to human asthma.
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[Experimental-morphologic study of depressed fracture of the skull. Experimental model].
Experimental skull bone models were made and depressed fractures were created. The morphological reactions of the skull bone models were observed to be the same as in human skulls, that is, that the fractures of the inner side were always larger than those of the outer side as a result of the direction of the impacting forces (a so-called classical type of reversed "V" form). The reason for the reversed "V" form of the depressed human skull fractures was discovered by means of these model studies. The reversed "V" form is due to the "HSH" morphological structure. It will be now be necessary to correct the error in textbooks regarding the depressed fractures, especially morphological illustrations.
Fractures, Open↗
Autoimmunity in multiple slcerosis: do we have an experimental model?
Experimental autoimmunity of the CNS has been well characterized--the antigen has been identified, effector cell specificity has been defined, and the relationship between cellular sensitization and antibody production has been partially clarified. In the guinea pig, experimental allergic encephalomyelitis (EAE) is induced by one injection of myelin basic protein in complete Freund's adjuvant (BP/CFA). If BP/CFA is preceded by repeated injections of basic protein in incomplete Freund's adjuvant (BP/IFA), EAE is not induced; the guinea pigs survive and ultimately produce antibody. Induction and prevention of EAE as well as antibody induction by this schedule are dependent on the presence of the intact encephalitogenic (T-cell) site in the polypeptide used for sensitization and preimmunization. In contrast, B cell sites (those peptide sequences which bind antibody) are independent of the T-cell site. At least 5 specific antigenic regions (B-cell sites) have been demonstrated in the BP molecule. High mycobacteria levels bypass the specificity requirement of helper T-cells but cannot bypass the specificity requirement of effector T-cells. In spite of the sophisticated immunologic techniques available, our knowledge of humoral and cellular sensitivity in multiple sclerosis (MS) patients is very limited. The experimental demonstration of an analogy between EAE and MS is weak: a) Demonstration of BP-sensitized cells or BP-specific antibodies in peripheral blood of MS patients has not been successful. b) Anti-myelin serum factors reported to be associated with both disease states (experimental autoimmunity and MS) are clearly not identical. Nevertheless, successful treatment of EAE in animals by BP/IFA injections has encouraged consideration of clinical trials to test the therapeutic value of BP injections in MS patients. If successful, the question will be answered: if unsuccessful, the dilemma still remains.
Adjuvants, Immunologic↗
Patency, blood flow and histologic characteristics in end-to-end and end-to-side arteriovenous fistulas. Comparisons in an experimental model.
Experimental arteriovenous fistulas of end-to-end (ETE) and end-to-side (ETS) type were created with microsurgical technique in rabbits between the carotid artery and the facial vein. Blood pressure and blood flow through the fistulas were registered during the operation and the flow capacity (flow/BP) was calculated. Evaluation was made at 2 hours, 1 day, 1 month and 3 months. Immediately after completion of the anastomosis there was no statistically significant difference in blood flow capacity between the ETE and the ETS group. At 1 month the flow capacity had increased significantly in the ETS, but not in the ETE group. At 3 months 3/5 of the ETS anastomoses remained patent, but all the ETE types were occluded. Histologic findings included severe intimal thickening at the anastomotic level and on the venous side of the anastomosis at 1 and 3 months. The study indicated that late blood flow and patency may be greater in ETS than in ETE arteriovenous fistulas.
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Valva ileocaecalis: preservation during ileocolonic surgery employing a rodent experimental model.
Experimental and clinical data suggest that the valva ileocaecalis under neurogenic and hormonal influences, modulates antegrade and retrograde flow of succus entericus. A priori reasoning suggests that this function may influence nutrient absorption by and intraluminal endogenous microbial flora within the ileum. The hypothesis to be tested was, can anatomical and functional integrity of the valva ileocaecalis be preserved during the performance of a right hemicolectomy with reestablishment of intestinal continuity via a cecocolostomy? The methodology involved utilization of Lewis male rats weighing approximately 500 gm. General anesthesia was induced for all procedures. The animals were randomly assigned to three groups (10 animals/group): (A) sham operation; (B) pericecal dissection (preservation of the arteria et vena ileocolica); and (C) periileal dissection (ligation of the aforementioned vessels). Celiotomy was performed employing standard clean techniques, and was accompanied by a right hemicolectomy and an end-to-end or end-to-side cecocolostomy. Function of the heterotopic valva ileocaecalis was assessed 6-12 weeks post-operatively employing radiographic criteria (fluoroscopic analysis after intraluminal instillation of barium sulfate). Light microscopic analysis was performed subsequent to the radiographic studies. Periileal dissection associated with ligation of the arteria et vena ileocolica uniformly resulted in anastomotic disruption. Pericecal dissection associated with preservation of those vessels resulted in uniform anastomotic integrity, although two animals succumbed secondary to pneumonitis within 5 post-operative days. Radiographic analysis of the heterotopic valva ileocaecalis revealed intermittent antegrade and no retrograde flow of contrast material, which suggested functional integrity. Qualitative light microscopic analysis revealed architectural integrity.(ABSTRACT TRUNCATED AT 250 WORDS)
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A morphologic comparison of three experimental models of experimental allergic encephalomyelitis with multiple sclerosis.
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[An experimental model of pleural cancer. Value of orthotopic implantation of human tumor tissue in nude mice].
Pleural cancers are tumours which are frequently refractory to all treatment. Faithful animal models (experimentally reproducing the human disease) are necessary to study the natural history of this disease and to test standard or experimental treatments. The athymic bald mouse is currently used for the construction of experimental models because it avoids immunological rejection. Initially murine models were constructed following subcutaneous injection of cloned cells then implantation of tumour fragments. The tumours obtained are not superimposable on the human disease in terms of local, regional or metastatic development and the results from these studies, using such models, are difficult to transpose to humans. It is possible to implant fragments of histologically intact human tumour into the pleura of bald mice. This orthoptic (site for site) transplantation enables one to obtain in the mouse a tumour which tends to conserve the biological characteristics of the original tumour and to develop locally, regionally and at distance in a fashion which is similar to the human disease. In spite of the inherent limits of immunotolerance of the host and thus difficulties of extrapolation to man, this review attempts to point out the place for these models and for an understanding of the therapy of pleural cancers.
Adenocarcinoma↗
Gene delivery to the lung by means of syngeneic fibroblasts: an experimental model.
An experimental model, in which exogenous gene expression in the lung is achieved, has been established. A fibroblast cell line was transfected with the lacZ gene and was administered to syngeneic mice by either intravenous or intratracheal injection. Enzyme-linked immunosorbent assay and histochemical detection of beta-galactosidase revealed efficient gene delivery to the lung by either route. Kinetic studies demonstrated that the expression peaked immediately after the injection, and this high level was maintained for 7 days by intratracheal and for 14 days by intravenous administration. This system may have potential relevance for certain experimental models requiring specific gene delivery to the lung.
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Hypotonic intrapleural cisplatin chemotherapy as treatment for pleural carcinomatosis in an experimental model.
An experimental model of intrapleural (i.pl.) chemotherapy using hypotonic solutions of sodium chloride was developed as a treatment for malignancies in the pleural cavity. In the current study, isotonic (308 mOsm/L), hypotonic (154 mOsm/L) and super-hypotonic (62 mOsm/L) solutions that contained equal amounts of cisplatin (CDDP) were prepared for an evaluation of their therapeutic efficacy and the pharmacokinetics of the drug. After the i.pl. injection of solutions of CDDP into mice with i.pl. tumors, we found that the amount of platinum taken up by tumor cells was significantly higher as the osmolarity of the solution was reduced. Hypotonic conditions continued for 1 hour after i.pl. injection of hypotonic solution. The maximum concentration (Cmax) and the area under the curve of concentration versus time (AUC) for platinum in the plasma was significantly higher in rats given CDDP in a hypotonic solution than in rats given the drug in an isotonic solution. The duration of survival of ddy mice with i.pl. tumors that were given i.pl. CDDP in solutions of lower osmolarity was significantly longer than that of mice given CDDP in an isotonic solution. These results indicate that use of a hypotonic solution might enhance the therapeutic efficacy of CDDP in an experimental model of pleural carcinomatosis. This procedure also seems promising as a prophylactic and therapeutic modality for treatment of patients with i.pl. malignancies.
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Evidence for common autoimmune disease genes controlling onset, severity, and chronicity based on experimental models for multiple sclerosis and rheumatoid arthritis.
The pathogenicity of multiple sclerosis is still poorly understood, but identification of susceptibility genes using the animal model experimental allergic encephalomyelitis (EAE) could provide leads. Certain genes may be shared between different autoimmune diseases, and identification of such genes is of obvious importance. To locate gene regions involved in the control of EAE and to compare the findings with the susceptibility loci recently identified in a model for rheumatoid arthritis (pristane-induced arthritis), we made crosses between the encephalomyelitis- and arthritis-susceptible rat strain DA and the resistant E3 strain. Genetic analysis of animals produced in a F2 intercross identified 11 loci associated with specific EAE-associated traits. Interestingly, five of these loci were situated at the same position as major loci controlling pristane-induced arthritis and showed similarities in inheritance pattern and subphenotype associations. Our results show that different phases of EAE are controlled by different sets of genes and that common genes are likely to be involved in different autoimmune diseases.
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