A technique for the selection of long-acting antimalarial compounds using a rodent malaria model.
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Yellow fever 17D as a vaccine vector for microbial CTL epitopes: protection in a rodent malaria model.
The yellow fever vaccine 17D (17D) is safe, and after a single immunizing dose, elicits long-lasting, perhaps lifelong protective immunity. One of the major challenges facing delivery of human vaccines in underdeveloped countries is the need for multiple injections to achieve full efficacy. To examine 17D as a vector for microbial T cell epitopes, we inserted the H-2K(d)-restricted CTL epitope of the circumsporozoite protein (CS) of Plasmodium yoelii between 17D nonstructural proteins NS2B and NS3. The recombinant virus, 17D-Py, was replication competent and stable in vitro and in vivo. A single subcutaneous injection of 10(5) PFU diminished the parasite burden in the liver by approximately 70%. The high level of protection lasted between 4 and 8 wk after immunization, but a significant effect was documented even 24 wk afterwards. Thus, the immunogenicity of a foreign T cell epitope inserted into 17D mimics some of the remarkable properties of the human vaccine. Priming with 17D-Py followed by boosting with irradiated sporozoites conferred sterile immunity to 90% of the mice. This finding indicates that the immune response of vaccine-primed individuals living in endemic areas could be sustained and magnified by the bite of infected mosquitoes.
Animals↗
Activation of the rostral ventrolateral medulla in an acute anesthetized rodent strychnine model of allodynia.
UNLABELLED: After the administration of intrathecal strychnine, allodynia is manifested as activation of supraspinal sites involved in pain processing and enhancement of cardiovascular responses evoked by normally innocuous stimuli. The objective of this study was to investigate the effect of strychnine-induced allodynia on adrenergic neuronal activity in the C1 area of the rostral ventrolateral medulla (RVLM), a major site involved in cardiovascular regulation. The effect of intrathecal strychnine (40 microg) or saline followed by repeated hair deflection to caudal lumbar dermatomes in the urethane-anesthetized rat was assessed by measuring voltammetric changes in the RVLM catechol oxidation current (CA x OC), mean arterial pressure (MAP), and heart rate (HR). After the administration of intrathecal strychnine, hair deflection evoked a significant and sustained increase in the RVLM CA x OC and MAP (peak 146.4%+/-5.6% and 159%+/-18.4% of baseline, respectively; P < 0.05). There was a nonsignificant increase in HR (peak 128%+/-8.2%). In the absence of hair deflection, there was no demonstrable change. Intrathecal saline-treated rats failed to demonstrate changes in RVLM CA x OC, MAP, or HR. In the present study, we demonstrated that, after the administration of intrathecal strychnine, innocuous hair deflection evokes temporally related neuronal activation in the rat RVLM and an increase in MAP. This suggests that the RVLM mediates, at least in part, the cardiovascular responses during strychnine allodynia. IMPLICATIONS: Neural injury-associated pain, as manifested by allodynia, is resistant to conventional treatment. In a rat model of allodynia, we demonstrated activation of the brain region involved in sympathetic control. Innovative therapies that target this region may be successful in managing this debilitating condition.
Anesthesia↗
Protocol of a thromboembolic stroke model in the rat: review of the experimental procedure and comparison of models.
RATIONALE AND OBJECTIVE: Different models to study the pathophysiology of cerebral ischemia and to evaluate therapeutic strategies exist. Described is the detailed procedure of a thromboembolic stroke model in the rat most closely resembling human embolic stroke and compare the model to other equivalent rodent models. MATERIALS AND METHODS: An evaluation of a new thromboembolic stroke model was performed on 35 male Wistar rats. After preparation of the carotid artery, a catheter was introduced into the external carotid artery. During injection of autologous, fibrin-rich emboli into the internal carotid artery the common carotid artery was temporarily occluded. Regional cerebral blood flow (rCBF) and lesion size were determined. RESULTS: Twelve fibrin-rich blood clots of 1.5 mm in length were necessary in order reliably to occlude the origin of the middle cerebral artery. A stable decrease of rCBF and lesion size was confirmed by autoradiography, diffusion, and perfusion MRI, TTC-staining, biochemical imaging, and histology. CONCLUSION: In this animal model, the situation of human cerebral ischemia is simulated closely. The model is suitable for investigations of the pathophysiology of stroke and facilitates studies on the effects of thrombolytic therapy.
Animals↗
Toward a sutureless vasovasostomy: use of biomaterials and surgical sealants in a rodent vasovasostomy model.
PURPOSE: With 500,000 to 800,000 vasectomies performed annually and a reversal rate of 3% to 8% vasectomy reversal has become a commonly performed procedure. Two-layer microsurgical vasovasostomy remains the gold standard for surgical reconstruction of the vas. However, this procedure is technically demanding and time-consuming. We determined the ability of biomaterials and surgical sealants to decrease the number of sutures used, enhance anastomosis watertightness and decrease operative time. MATERIALS AND METHODS: Adult male Wistar rats underwent vasectomy 2 weeks prior to vasovasostomy. Standard 2-layer microsurgical repair was performed in control animals. Experimental groups underwent 3-suture mucosal approximation and then completion of the anastomosis with a biomaterial membrane and/or synthetic sealant. The rats were sacrificed 9 weeks after vasovasostomy. Anastomotic patency was assessed functionally by the presence of motile sperm in the vas distal to the testes and anastomosis, and mechanically by methylene blue vasogram. The presence and size of sperm granulomas were also recorded. RESULTS: Microsurgical vasovasostomy required significantly less time when biomaterial (42.7 minutes) or sealant (40 minutes) was used compared to the standard sutured group (102.5 minutes, each p < 0.001). There was no difference in patency between the standard sutured and biomaterial groups (90% vs 92%). Patency was significantly lower in the sealant groups, that is 70% in the suture, biomaterial and sealant group, and 75% in the suture and sealant group. The biomaterial group had only 1 sperm granuloma in 12 procedures, which was significantly better than the 7 in the control group (p <0.001). CONCLUSIONS: Using a biomaterial wrap during vasovasostomy resulted in significantly decreased operative time and fewer sperm granulomas than in the control group. Sealants were not effective. Biomaterial wrap may support vasovasostomy and by decreasing leakage improve the outcome.
Animals↗
Plasmodium chabaudi: a rodent malaria model for in-vivo and in-vitro cytoadherence of malaria parasites in the absence of knobs.
The ability of Plasmodium chabaudi infected erythrocytes to bind to endothelial cells in vivo and to various murine cell lines in vitro is described. A procedure for the selective recovery of a sequestering subpopulation of schizont-infected erythrocytes from hepatic sinusoids of BALB/c mice, using a combination of body perfusion, trypsin treatment and Percoll density centrifugation was developed. The serial subinoculation of such a subpopulation was used to select for a clone of parasites (strain AJJ) with considerably better cytoadherent characteristics than the parent line (strain AJ). In contrast, it was demonstrated that another clone (PC7), showed no cytoadherence in vivo or in vitro. This study shows that parasite induced alterations occurred on the surface of erythrocytes infected with late developmental stages of P. chabaudi. The antigenicity of these molecules in the infected mouse was demonstrated using immune serum and affinity chromatography. Cytoadherence and surface antigenic changes in P. chabaudi schizont-infected erythrocytes were demonstrated in the absence of the submembranous 'knobs' associated with cytoadherence in P. falciparum.
Animals↗
Sympathetic modulation of sensory nerve activity with age: human and rodent skin models.
1. Sensory nerves serve an afferent role and mediate neurogenic components of inflammation and tissue repair via an axon reflex release of sensory peptides at sites of injury. Dysfunction of these nerves with age could contribute to delayed tissue healing. 2. Complementary animal and human skin models were used in the present studies to investigate changes in the modulation of sensory nerve function by sympathetic efferents during ageing. Laser Doppler flowmetry was used to monitor neurogenic skin vascular responses. 3. The animal model used skin of the hind footpad of anaesthetized rats combined with electrical stimulation of the sciatic nerve, while the human model comprised capsaicin electrophoresis to the volar surface of the forearm. Sympathetic modulation was effected by systemic phentolamine pretreatment in animals and local application in the human model. 4. The results obtained from the human model confirmed the reported decline in sensory nerve function and showed no change in sympathetic modulation with age. The results from the animal model confirm and expand results obtained from the human model. 5. The use of low (5 Hz) and high (15 Hz) frequency electrical stimulation (20 V, 2 ms for 1 min) revealed a preferential response of aged sensory nerves to low-frequency electrical stimulation parameters with differential sympathetic modulation that is dependent on the frequency of stimulation.
Adult↗
Rodent nutritional model of steatohepatitis: effects of endotoxin (lipopolysaccharide) and tumor necrosis factor alpha deficiency.
BACKGROUND AND AIMS: Intestinal endotoxin (lipopolysaccharide) is thought to contribute to liver injury in both alcoholic and nonalcoholic steatohepatitis (NASH). Tumor necrosis factor alpha (TNFalpha) is an important mediator of this process and is considered central to the inflammatory response in NASH. This study aimed to investigate the effects of lipopolysaccharide on liver injury in the methionine choline deficient (MCD) nutritional model of NASH, and to determine if TNFalpha is required for the development of steatohepatitis in this model. METHOD: Male C57/BL6 mice received a MCD diet for 4 weeks, whilst a control group received an identical diet supplemented with 0.2% choline bitartrate and 0.3% methionine. At 4 weeks, mice received either an intraperitoneal injection of lipopolysaccharide (0.5 microg/g body mass) or sterile saline, and were killed 24 h thereafter. In a separate study, TNFalpha knockout and wild type C57BL/6 mice received either MCD or control diets for 4 weeks. Serum transaminase levels, liver histology (steatosis, inflammation and apoptosis), hepatic triglyceride concentration and hepatic lipid peroxidation products (conjugated dienes, lipid hydroperoxides and thiobarbituric reactive substances, free and total) were evaluated. RESULTS: Intraperitoneal administration of lipopolysaccharide augmented serum alanine aminotransferase (ALT) levels (P<0.02), hepatic inflammation (P<0.025), apoptosis (P<0.01) and free thiobarbituric acid reactive substances (P<0.025) in MCD mice. TNFalpha knockout mice fed the MCD diet developed steatohepatitis with histological and biochemical changes similar to those seen in wild type counterparts. CONCLUSIONS: Lipopolysaccharide augments liver injury in MCD mice, and TNFalpha is not required for the development of steatohepatitis in MCD mice.
Alanine Transaminase↗
Analysis of immune responses against T- and B-cell epitopes from Plasmodium falciparum liver-stage antigen 1 in rodent malaria models and malaria-exposed human subjects in India.
Liver-stage antigen 1 (LSA-1) is a potential vaccine candidate against preerythrocytic stages of malaria. We report here the immunogenicity of linear synthetic constructs delineated as T(H)-cell determinants from the nonrepeat regions of Plasmodium falciparum LSA-1 in murine models and human subjects from areas where malaria is endemic in Rajasthan State, India. Seven peptide constructs (LS1.1 to LS1.7) corresponding to predicted T-cell sites from both the N- and C-terminal regions and peptide LS1R from a repeat region of PfLSA-1 were synthesized to analyze the cellular immune responses. These linear peptides were also tested for humoral responses in order to determine if there were any overlapping B-cell epitopes in the predicted T-cell sites. Most peptides induced cellular responses in peptide-immunized BALB/c and C57BL/6 mice as measured by proliferation and cytokine analysis. Cross-reactive T-cell recognition of P. falciparum-based peptides in Plasmodium berghei-immune animals was evaluated, but only one peptide, LS1.2 (amino acids 1742 to 1760) triggered T-cell proliferation and interleukin-2 and gamma interferon secretion in P. berghei-immune splenocytes of BALB/c and C57BL/6 mice as well as in Thamnomys gazellae (natural host of P. berghei ANKA). In an enzyme-linked immunosorbent assay with the peptides, only one peptide, LS1.1, was recognized by anti-P. berghei liver-stage serum. Three peptides (LS1. 1, LS1.2, and LS1.3) of the eight peptides tested in this study were recognized by a relatively large percentage of P. falciparum-exposed human subjects; the reactivities ranged from approximately 45% for LS1.3 to approximately 60% for LS1.1 and LS1.2. Interestingly, all of the eight putative T-cell determinants were also recognized by the sera collected from malaria patients, although the response was variable in nature. These T(H)- and B-cell epitopes may be of potential value for preerythrocytic antigen-based malaria subunit vaccine formulations.
Adolescent↗
Patupilone induced vascular disruption in orthotopic rodent tumor models detected by magnetic resonance imaging and interstitial fluid pressure.
PURPOSE: Evaluation of vascular disruptive activity in orthotopic models as potential surrogate biomarkers of tumor response to the microtubule-stabilizing agent patupilone. EXPERIMENTAL DESIGN: Mice bearing metastatic B16/BL6 melanoma and rats bearing mammary BN472 tumors received vehicle or efficacious patupilone doses (4 and 0.8-1.5 mg/kg i.v., respectively). Tumor vascularity assessment by dynamic contrast-enhanced or dynamic susceptibility contrast magnetic resonance imaging and interstitial fluid pressure (IFP) occurred at baseline, 2 days (mice and rats), and 6 days (rats) after treatment and were compared with histologic measurements and correlated with tumor response. RESULTS: In B16/BL6 metastases, patupilone (4 mg/kg) induced a 21 +/- 5% decrease (P < 0.001) in tumor blood volume and a 32 +/- 15% decrease (P = 0.02) in IFP after 2 days and reduced tumor growth and vessel density (>42%) after 2 weeks (P < or = 0.014). Patupilone dose-dependently inhibited BN472 tumor growth (day 6) and reduced IFP on days 2 and 6 (-21% to -70%), and the percentage change in IFP correlated (P < 0.01) with the change in tumor volume. In both models, histology and vascular casts confirmed decreases in tumor blood volume. One patupilone (0.8 mg/kg) administration decreased (P < 0.01) tumor IFP (54 +/- 4%), tumor blood volume (50 +/- 6%), and vessel diameter (40 +/- 11%) by day 6 but not the apparent diffusion coefficient, whereas histology showed that apoptosis was increased 2.4-fold and necrosis was unchanged. Apoptosis correlated negatively (P < 0.001) with IFP, tumor blood volume, and tumor volume, whereas tumor blood volume and IFP were correlated positively (P = 0.0005). CONCLUSIONS: Vascular disruptive effects of patupilone were detected in situ using dynamic contrast-enhanced or dynamic susceptibility contrast magnetic resonance imaging and IFP. Changes in IFP preceded and correlated with tumor response, suggesting that IFP may be a surrogate biomarker for patupilone efficacy.
Animals↗
Reduction of vein graft disease using photodynamic therapy with motexafin lutetium in a rodent isograft model.
BACKGROUND: Motexafin lutetium (Lu-Tex) is a photosensitizer that targets atheromatous plaque. Subsequent photoactivation (photodynamic therapy [PDT]) induces local cytotoxic effects. The aim of the present study was to investigate whether Lu-Tex targets vein graft intimal hyperplasia and whether subsequent photoactivation attenuates the disease process. METHODS AND RESULTS: The subcellular localization of Lu-Tex and postillumination viability were studied in cultured human vein graft smooth muscle cells. Inferior vena cava-grafted rats were injected with Lu-Tex (10 mg/kg) 4 or 12 weeks after grafting. Biodistribution was assessed in a subgroup 24 hours after administration. Light therapy (742 nm) was performed 24 hours after Lu-Tex injection by illuminating intraperitoneally placed isografts using a laparotomy. Animals were divided into the following 4 groups: PDT (n=15), Lu-Tex injection and laparotomy (n=13), light treatment (n=14), and laparotomy only (n=13). Grafts were harvested 14 days after treatment for histochemical analysis. Lu-Tex localized within subcellular organelles of smooth muscle cells, and subsequent photoactivation induced cell death via apoptosis. The Lu-Tex concentrations present in the vein grafts were 9.3 times higher than those in the normal inferior vena cava. Postoperative PDT at 4 weeks after surgery significantly reduced the intima/media ratio, whereas treatment at 12 weeks did not reduce the intima/media ratio. Activated macrophages were observed 4 weeks after grafting; however, a significant reduction occurred in these cells by 12 weeks. The mechanism by which PDT works may be related to the presence of activated macrophages. CONCLUSIONS: PDT significantly reduces the intima/media ratio in the early phase of vein graft disease. Lu-Tex-mediated PDT may be a viable method for the attenuation of atherosclerotic disease in vein grafts.
Animals↗
Immunization experiments using the rodent caries model.
Taken together, the immunization experiments which have been performed in the rat caries model system appear to suggest a correlation between the presence of salivary antibody to S mutans and reductions in caries caused by these bacteria. However, the multifactorial nature of this disease does not permit at present the conclusion that the presence of this antibody is both necessary and sufficient to give rise to the demonstrated effects on pathogenesis. To clarify the role of salivary antibody, several refinements may be required in the current model. Immunization procedures that elicit only a local antibody response would both simplify interpretations of effects and would be more desirable for use as a vaccine. Such procedures might include intraductal installation of antigen in the parotid gland which has been demonstrated to result in this type of response. An additional refinement stems from the knowledge that the kinds of immunization procedures currently used stimulated both cellular immune and soluble antibody systems, potentially giving rise to a rather broad spectrum of immune responses. Therefore, it might be useful to study the effects on S mutans pathogenesis in rats in which certain of these responses have been repressed, for example, by thymectomy, antilymphocyte serum, and so on. Also, each of these approaches would be measurably enhanced by more sensitive techniques to monitor immunological events in the oral cavity. Refinements in the selection and use of relevant antigens of S mutans also are necessary to delineate the in vivo mechanism of immunological interference in the pathogenesis of cariogenic streptococci. Approaches involve the use of purified GTF antigens or cell surface antigens both in the investigation of these mechanisms in in vitro models using antibody specifically directed to these antigens and in rat immunization experiments using immunogenic preparations of these materials. In addition, alterations in the diet and challenge dosage of infecting cariogenic organisms might permit more sensitive detection of effects in vivo. Clearly, the evidence suggests immunological interference with S mutans pathogenesis in the rat model system. However, several gaps exist in our basic understanding of this interference and of the appropriate system in which to observe these effects. The potential significance of this phenomenon should spur efforts to fill these gaps to establish definitively the role of immunity as an ecological determinant in the oral cavity.
Animals↗
The localization and functional contribution of striatal aromatic L-amino acid decarboxylase to L-3,4-dihydroxyphenylalanine decarboxylation in rodent parkinsonian models.
L-3,4-Dihydroxyphenylalanine (L-dopa) is the mainstay of therapy for patients with Parkinson's disease (PD), and mediates its primary effects through conversion into dopamine by aromatic L-amino acid decarboxylase (AADC). Given the loss of AADC-containing nigrostriatal dopaminergic neurons in PD, however, the location of residual AADC that converts L-dopa into dopamine remains controversial. The first objective of this study was to establish the presence of AADC expression in striatal neurons and glia using reverse transcriptase and PCR. Transcripts for the neuronal but not nonneuronal forms of AADC were detected in striatal tissue, cultured striatal neurons, and glia. We then examined whether this striatal AADC expression represents a physiologically significant source of dopaine production. No dopamine release was detected following incubation of striatal cultures with L-dopa or transduction with adenovirus expressing tyrosine hydoxylase. Our data establish the presence of AADC expression in the striatum both in vivo and in vitro, but suggest that striatal components do not represent a primary source of L-dopa decarboxylation following nigrostriatal denervation in rats. Understanding the source and localization of AADC is important in understanding the complications of L-dopa therapy and in designing rational therapeutic strategies for PD, including cellular transplantation and gene therapy.
Adenoviridae↗
Optical intrinsic signal imaging in a rodent seizure model.
The authors studied seizure activity with optical intrinsic signal (OIS) imaging in a rat seizure model. OIS, which measures vascular and metabolic effects associated with neuronal activity, showed significant cortical reflectance changes from penicillin-induced seizures, and correlated well with EEG epileptiform discharges. Furthermore, OIS changes often preceded initial EEG spikes. These observations suggest that OIS is well coupled with seizure activity, and may provide sensitive cues for seizure detection.
Animals↗
Alcohol and anxiety: effects on offensive and defensive aggression.
Inconsistencies in the effects of alcohol on aggression in rodent models suggest that this effect is mediated through some other factor that is differentially involved in the various tests. The patterning of alcohol enhancement of aggression suggests that this may be most apparent in tests in which defensiveness or anxiety act to reduce aggression. Thus, an understanding of the relationship between alcohol and aggression may also involve determination of alcohol effects on anxiety. New ethoexperimental models of anxiety in rodents involve the measurement of a range of defensive behaviors to approaching, contacting predators, or to situations associated with (absent) predators. A Fear/Defense Test Battery, measuring the former, showed little, and inconsistent, response to traditional (benzodiazepine) or nontraditional (5-HT1A agonist) anxiolytics. However, an Anxiety/Defense Test Battery, measuring the latter, produced an "anxiolytic profile" of changes seen consistently to both traditional and nontraditional anxiolytics, but not to nonanxiolytic drugs. Alcohol (0.6 and 1.2 g/kg) altered the four behaviors of the "anxiolytic profile" in a manner consistent with the effects of diazepam (2.0 and 4.0 mg/kg), indicating that it is also anxiolytic. The consistency of alcohol and diazepam effects on anxiety provide a possible mechanism for their somewhat similar effects on aggression. However, alcohol at nonsedative doses, but not diazepam, additionally enhances defensive attack. Although defensive attack is behaviorally and neurally different from offensive aggression, the two are not separated in analyses of human "aggression," suggesting that alcohol effects in the latter may also be mediated by changes in defensive attack.
Aggression↗
Other potentially useful rodents as models for the study of human diabetes mellitus.
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Animals↗
Reliability of rodent animal models in biomedical research.
Despite the discrepancies observed between the data generated from humans and animals, it is a usual practice that the results obtained from animal models are extrapolated on humans. This review stresses that while animal models are essential for the research and development, a critical caution needs to be practiced in interpreting the results. Uncritical reliance on the results of animal experimentation can be dangerously misleading and has resulted in damages to human health in several cases. This review also discusses the role of certain confounding factors in using animal models due to which appropriate precautions need to be taken while deciding to conduct a study using animal models and caution is warranted in extrapolating the data obtained from pre-clinical studies on humans.
Animals↗
Transgenic technology in farm animals--progress and perspectives.
Current applications of gene transfer in farm animals include the improvement of product quality and quantity, disease resistance, the production of valuable proteins in the mammary gland or other organs, the genetic modification of pigs for xenotransplantation and the generation of new animal models in cases where rodent models are not sufficient for studying the problem under evaluation. Although DNA microinjection into pronuclei of zygotes from various farm animal species has happened since 1985, the efficiency of this method is low. Further drawbacks are related to the random integration process which may cause mosaicism, insertional mutations and varying expression due to position effects. Sperm-mediated gene transfer is not routinely established yet, although the mechanisms of binding and internalisation of DNA by sperm cells is becoming increasingly clearer. New protocols for the use of retroviral vectors to infect metaphase II oocytes which are subsequently fertilised resulted in efficient production of transgenic cattle. In spite of extensive efforts to establish pluripotent stem cells from farm animal species, no germ-line competent cells have been reported in mammalian species other than mouse so far. However, recent success in cloning sheep, cattle, goats and pigs from cultured cells provides an alternative route for efficient and targeted genetic modifications of farm animals.
Animals↗