The inflammatory reaction in the airways in an animal model of the late asthmatic response

The late asthmatic response is defined as airway obstruction that occurs hours after antigen exposure in some atopic asthmatics. The importance of this reaction is that the airway obstruction may be severe, prolonged, and difficult to control unless corticosteroids are employed. In addition, this response may lead to an increase in airway reactivity. To investigate the immunopathogenesis of this disorder, an animal model in rabbits was developed. In this model, antigen-specific IgE was associated with the late asthmatic response and antigen-specific IgG was associated with blunting of the reaction. Antigen challenge of immune rabbits led to edema within the large airways shortly after antigen exposure, with infiltration of inflammatory cells (neutrophils and eosinophils) into the large and small airways during the late response. The infiltrates became more mononuclear with time and resolved over 10 days. As in humans, the late response was associated with an increase in airway reactivity and correlated temporally with infiltration of the airways with neutrophils and eosinophils. The contribution of granulocytic cells to the airway responses to antigen was studied by granulocyte depletion, which prevented both the late response and the heightened airway reactivity. In addition, transfusion of a neutrophil-rich population of white cells into granulocytopenic immune rabbits restored both responses. Thus, in this animal model, the antigen-induced late asthmatic response and subsequent increase in airway reactivity were dependent on the presence of granulocytes at the time of exposure to antigen.     

Evaluation of animal models for the study of exercise-induced muscle enlargement

Skeletal muscle is known to enlarge in response to high-resistance training programs in humans. Study of the cellular mechanisms of muscle enlargement and the adaptations of muscle to strength-training programs has been difficult because of the need to analyze entire muscles. This precludes the use of human subjects in many experiments of this nature. Several animal models have been developed for the study of muscle enlargement; these models basically fall into three categories: 1) stretch hypertrophy, 2) compensatory hypertrophy, and 3) exercise-induced hypertrophy. This review attempts to analyze these models as models of muscle enlargement produced by strength training in humans. Three areas must be considered when evaluating animal models of human muscle enlargement produced by strength training: 1) response topography, 2) magnitude of enlargement, and 3) muscle fiber adaptations produced as a result of the enlargement. Based on these considerations, it is concluded that none of the animal models currently in use truly represents the human strength-training situation under all conditions. All three models, however, provide valuable information about the plasticity of skeletal muscle in response to a broad spectrum of muscle enlargement.     

Animal models for the study of immunity in human filariasis

A major challenge to the development of vaccines against human lymphatic filariasis and onchocerciasis is to direct the immune response toward elimination of the early, prepathogenic larval stages and away from responses that mediate pathology. In this review, James Lok and David Abraham discuss the various animal models that have been used to investigate the pathways leading to immunity, immunological tolerance and chronic pathology in these diseases. Owing to the strict host specificities of the human-dwelling filariae, no single model serves to duplicate exactly all these aspects. Nevertheless, it has been possible to demonstrate a protective immune response invoked by and directed against incoming third-stage larvae of both lymphatic and skin-dwelling filariae. The fact that subsets of the sequelae of human filarial infection can be duplicated in animal systems should also aid in unravelling the mechanisms determining the course of infection and in ensuring that vaccine candidates do not produce an inappropriate immunopathological response. A proposed scheme for using animal models in screening candidates for a vaccine against Onchocerca volvulus is presented.     

Immune response in dog 2 effect of dose of antigen on antibody production.

The primary antibody response of dogs and rabbits to both 'H' and 'O' antigens of Salmonella typhosa following intravenous injection with a formalin killed vaccine from 2.4 x 10(6) to 2.4 x 10(10) organisms/kg body weight was analysed. The animals were restimulated 80 days later with various vaccine concentrations. The lgM anti-'O' and lgG anti-'H' and 'O' antigens in the dogs, were significantly weaker in both primary and secondary response than the comparable rabbit group. Primary lgM anti-'H' response in the dog was found to be greater, equal, or less than that observed in the rabbit. A closer analysis of the primary response indicated that both animal species show the same latent period and doubling time in respect of anti-'H', and the differences observed are probably the result of the number of progenitor cells stimulated by the antigen. On the other hand the suppressed response of the dog to 'O'-antigen is the result of an overall weaker response of this animal to the antigen. The secondary anti-'H' lgM response was found to be greater than, equal to, or less than the primary response in the same animal. The significant inhibition of this response was observed in those animals which received a high primary dose of antigen.     

Complementary idiotypy in the regulation of the immune response.

A new concept is presented for the interactions of two complementary antibodies in the immune response. These antibodies bind to each other by means of their variable sequence determinants and therefore are designated as complementary idiotypes. Under certain conditions, both complementary idiotypes are produced by the same animal at the same time. An idiotype can drastically affect the expression of the complementary idiotype in the animal, inducing a peripheral quench effect of antibody-binding activity and a central effect on the immunocompetent cell, which produces the complementary idiotype. It is proposed that complementary idiotypes might be induced during every immune response, thus playing an essential role in the regulation of the immune response.     

Rationale and design of the SMART Heart study

Left ventricular hypertrophy (LVH) is an independent risk factor for the development of heart failure, coronary heart disease and stroke. LVH develops in response to haemodynamic overload, e.g. hypertension. LVH was originally thought to start as an adaptive and beneficial response required to normalise wall stress. However, this concept has been challenged by recent animal experiments suggesting that any degree of LVH is detrimental for the preservation of cardiac function and survival. If confirmed in humans, these findings imply that an increase in LV mass should be prevented, e.g. by lifestyle or pharmacological interventions. To facilitate and optimise interventions, the SMART Heart study was recently set up to develop a prediction model, also involving single nucleotide polymorphism data, for the identification of subjects at high risk of developing LVH in hypertension. For this purpose 1000 subjects with chronic hypertension will undergo cardiac MR imaging. In addition, this study allows the extrapolation of animal experimental genetic research into the human situation. (Neth Heart J 2007;15:295-8).     

Dissociation by colchicine of the wet weight and the cGMP responses to estradiol in immature rat uterus

We previously reported on a positive correlation between two effects of estrogen on rat uterus, namely the early increases in cGMP and in water content of the organ suggesting that they were under the control of the same hormone sensitive regulatory process or linked by a cause to effect relationship. Up to now we were unable to find experimental conditions that would dissociate the two responses. In this work, immature Wistar rats were treated with colchicine (50 micrograms/animal) given at the same time as estradiol-17 beta (1 microgram/animal) or with estradiol alone. The experiments showed: (1) that the estradiol induced increase in uterine wet weight that occurs during the first 8 h after hormone injection was completely suppressed in the presence of colchicine indicating that it might depend on an intact microtubular system and (2) that, by contrast, the estrogen-induced increase in uterine cGMP remained unaffected by the colchicine presence. These data allow to conclude that the cGMP response to estradiol can be dissociated from the wet weight response and, therefore, that it is not controlled by the latter. From this and from data in the literature the hypothesis is proposed that the increase in uterine cGMP content might trigger the wet weight response, this possibly through a positive action on some microtubular function.     

Exploring the Validity of Proposed Transgenic Animal Models of Attention-Deficit Hyperactivity Disorder (ADHD)

Attention-deficit/hyperactivity disorder (ADHD) is a common, behavioral, and heterogeneous neurodevelopmental condition characterized by hyperactivity, impulsivity, and inattention. Symptoms of this disorder are managed by treatment with methylphenidate, amphetamine, and/or atomoxetine. The cause of ADHD is unknown, but substantial evidence indicates that this disorder has a significant genetic component. Transgenic animals have become an essential tool in uncovering the genetic factors underlying ADHD. Although they cannot accurately reflect the human condition, they can provide insights into the disorder that cannot be obtained from human studies due to various limitations. An ideal animal model of ADHD must have face (similarity in symptoms), predictive (similarity in response to treatment or medications), and construct (similarity in etiology or underlying pathophysiological mechanism) validity. As the exact etiology of ADHD remains unclear, the construct validity of animal models of ADHD would always be limited. The proposed transgenic animal models of ADHD have substantially increased and diversified over the years. In this paper, we compiled and explored the validity of proposed transgenic animal models of ADHD. Each of the reviewed transgenic animal models has strengths and limitations. Some fulfill most of the validity criteria of an animal model of ADHD and have been extensively used, while there are others that require further validation. Nevertheless, these transgenic animal models of ADHD have provided and will continue to provide valuable insights into the genetic underpinnings of this complex disorder.     

Transformation of a waiting schedule into a temporal regulation schedule (DRRD) by addition of external stimuli in the dog

Waiting schedules do not impose temporal regulation but condition the animal to give the operant response during a given time. At the end of the required delay, a positive discriminative stimulus is presented. The suspension of the response while the discriminative stimulus is being given suspension of the response while the discriminative stimulus is being given is accompanied by reinforcement. The transformation of a waiting schedule into a temporal regulation schedule is generally achieved by suppressing the external facilitating factors or by physically modifying them. Our study reveals that a similar transformation can be achieved in the dog by the addition of a further stimulus. This stimulus, which is physically exactly the same as the excitatory stimulus and which punctuates the waiting period, is randomly introduced into the temporal delay. The absence of reinforcement in response to the added stimulus should force the animal to regulate its behavior in time and the additional negative discriminative stimulus favours the expression of the active nature of the inhibation. The results show that subjects can differentiate their response durations according to stimuli that only differ according to temporal location. Thus this pattern resembles a DRRD schedule. The peak of responses at the time of the inhibition stimulus reveals considerable behavioral conflict : either the response must be maintained or the inhibition suppressed. The positive or negative resolution of this conflict reveals noteworthy aspects of the behavioural inhibition process.     

Xwnt-8 modifies the character of mesoderm induced by bFGF in isolated Xenopus ectoderm.

In Xenopus, growth factors of the TGF-beta, FGF and Wnt oncogene families have been proposed to play a role in generating embryonic pattern. In this paper we examine potential interactions between the bFGF and Xwnt-8 signaling pathways in the induction and dorsal-ventral patterning of mesoderm. Injection of Xwnt-8 mRNA into 2-cell Xenopus embryos does not induce mesoderm formation in animal cap ectoderm isolated from these embryos at the blastula stage, but alters the response of this tissue to mesoderm induction by bFGF. While animal cap explants isolated from non-injected embryos differentiate to form ventral types of mesoderm and muscle in response to bFGF, explants from Xwnt-8 injected embryos form dorsal mesodermal and neural tissues in response to the same concentration of bFGF, even if the ectoderm is isolated from the prospective ventral sides of embryos or from UV-ventralized animals. Our results support a model whereby dorso-ventral mesodermal patterning can be attained by a single mesoderm inducing agent, possibly bFGF, which is uniformly distributed across the prospective dorsal-ventral axis, and which acts in concert with a dorsally localized signal, possibly a Wnt protein, which either alters the response of ectoderm to induction or modifies the character of mesoderm after its induction.     

Early OspA immune complex formation in animal models of Lyme disease

Infection with Borrelia burgdorferi, the cause of Lyme disease, has been accompanied by a puzzling delayed antibody (Ab) response to B. burgdorferi antigens (Ags) including the abundant organism-specific outer surface proteins, such as the 31-kD OspA. In humans the response to nonspecific B. burgdorferi Ags has required 3-6 weeks. The response to OspA has rarely been detected by conventional methodology until months after infection, despite demonstrable T cell reactivity. Tick inoculation and low-dose intradermal inoculation animal models have been characterized by a comparable response to OspA. Using more sensitive biotin-avidin immunoblots and immune complex (IC) dissociation techniques, we demonstrated in humans that Ab to OspA is formed early but may remain at low levels or bound in IC. To see if this was a universal biologic response, animal models were analyzed by these methods. The results with mice, monkeys and rabbits show that IC Ab to OspA may be detected at the onset of infection. The data suggest that these animal models may be used to understand the immune response to B. burgdorferi and the pathogenesis of Lyme disease. With attention to unique B. burgdorferi Ags, these results are likely to have both clinical and diagnostic importance.     

Ventral ectoderm of Xenopus forms neural tissue, including hindbrain, in response to activin.

The peptide growth factor Activin A has been shown to induce complete axial structures in explanted blastula animal caps. However, it is not understood how much this response to activin depends upon early signals that prepattern the ectoderm. We have therefore asked what tissues can be induced in blastula animal caps by activin in the absence of early dorsal signals. Using whole-mount in situ hybridization, we compare the expression of three neural markers, N-CAM, En-2 and Krox-20 in activin-treated ectoderm from control and ventralized embryos. In response to activin, both normal and ventralized animal caps frequently form neural tissue (and express N-CAM) and express the hindbrain marker Krox-20. However, the more anterior marker, En-2, is expressed in only a small fraction of normal animal caps and rarely in ventralized animal caps; the frequency of expression does not increase with higher doses of activin. In all cases En-2 and Krox-20 are expressed in coherent patches or stripes in the induced caps. Although mesoderm is induced in both control and ventralized animal caps, notochord is found in response to activin at moderate frequency in control caps, but rarely in ventralized animal caps. These results support the idea that in the absence of other signals, activin treatment elicits hindbrain but not notochord or anterior neural tissue; and thus, the anterior and dorsal extent of tissues formed in response to activin depends on a prior prepatterning or previous inductions.     

A new approach to the analysis of complex dose-response relationships: a multivariate study of octopamine action on the leech Leydig neurone

Octopamine (OA) hyperpolarizes leech Leydig neurones but response amplitudes and thresholds vary. Associations between response, OA dose and other variables [initial resting potential, action potential (AP) frequency and amplitude, temperature, microelectrode resistance, position of ganglion along nerve cord, animal, treatment order] were examined using canonical correlation. A complex response was expressed by summing changes in membrane potential and AP frequency over 2 min of OA treatment. Only dose and ganglion position influenced this response. One significant canonical variate related dose to immediate changes in membrane potential and summed changes in AP frequency throughout the OA effect. Response to OA was greater in cells in posterior ganglia.     

Effect of anaesthetics on the sympathetic reflex.

i) In the awake animal, neither a late response nor a silent period could be evoked from the tibial nerve. Somatic afferentation with impulse trains failed to inhibit efferent sympathetic activity. On the other hand, vagal afferentation had an inhibitory action also in the awake animal. In the awake animal, the excitatory processes are dominant. ii) Urethan anaesthesia did not influence the sympathetic nervous processes; the reflex response were practically the same as in the awake animal. iii) Chloralose anaesthesia altered the sympathetic reflex observable in the awake animal. Somatic afferentation of low threshold voltage already elicited a late response and a silent period; in addition, a high degree of summation ability of silent periods was apparent. Thus, chloralose anaesthesia seems to raise the excitatory level of the sympathetic centres in the direction of inhibition. iv) Combined chloralose+urethan anaesthesia, under which investigations are usually performed, was seem to affect the reactivity of the sympathetic centres in the same way as did chloralose anaesthesia.     

Activation of human and murine B cells by anti-immunoglobulin antibody: dependence of the response on the preexisting level of B-cell activation

Previous reports of the response of B lymphocytes to soluble anti-immunoglobulin (anti-Ig) antibodies have yielded conflicting data. While most studies show activation of B cells, others have shown inhibitory effects. In the assay reported in this report, we were able to obtain widely diverse responses of human B-cell populations to anti-Ig antibody. An explanation of this variability was established by resort to an animal (murine) model. Mice maintained in a pathogen-free environment failed to respond or responded only weakly to anti-Ig antibody. Mice which had previously received heavy antigenic stimulation, but at the time of the experiment were not undergoing any known challenge, showed a marked positive response. Mice deliberately challenged with lipopolysaccharide (LPS) 24 hr prior to anti-Ig antibody exposure showed a high background mitogenesis in control cultures, which was inhibited by anti-Ig antibody. This preliminary study suggests that response to anti-Ig antibody differs in each phase of B-cell differentiation. In future studies it is hoped that this variability in response can be used to characterize different subsets of B-cell differentiation separated by physical or phenotypic parameters.     

Animal housing influences the response of bone to spaceflight in juvenile rats.

The rat has been used extensively as an animal model to study the effects of spaceflight on bone metabolism. The results of these studies have been inconsistent. On some missions, bone formation at the periosteal bone surface of weight-bearing bones is impaired and on others it is not, suggesting that experimental conditions may be an important determinant of bone responsiveness to spaceflight. To determine whether animal housing can affect the response of bone to spaceflight, we studied young growing (juvenile) rats group housed in the animal enclosure module and singly housed in the research animal holding facility under otherwise identical flight conditions (Spacelab Life Science 1). Spaceflight reduced periosteal bone formation by 30% (P < 0.001) and bone mass by 7% in single-housed animals but had little or no effect on formation (-6%) or mass (-3%) in group-housed animals. Group housing reduced the response of bone to spaceflight by as much as 80%. The data suggest that housing can dramatically affect the skeletal response of juvenile rats to spaceflight. These observations explain many of the discrepancies in previous flight studies and emphasize the need to study more closely the effects of housing (physical-social interaction) on the response of bone to the weightlessness of spaceflight.     

The use of an incremental repeated acquisition task to assess learning in children

The development of valid animal models of learning is especially important since learning is critical for nearly all aspects of human behavior and identifying appropriate surrogates provides additional opportunity to study various aspects of learning. Examining the factors that affect learning is often complicated by the need to administer the same task repeatedly across experimental conditions. Incremental repeated acquisition (IRA) tasks have been used extensively in animal research because they circumvent this problem by requiring a subject to learn different response chains repeatedly across sessions. The present study examined the association of age, sex of the participant, and IQ on the performance of an incremental repeated acquisition task in 837 children, aged 5-13 years. This task required children to learn to press four response levers in a specific sequence that was randomly chosen. Illumination of colored indicator lights signaled position in the required response chain. Initially, for the first link, only one of the four levers was correct: a response to it resulted in the delivery of a monetary reinforcer (5 cents). After mastery of the first link (i.e. three correct presses), the children were presented with a two-link response chain: a different lever had to be pressed before pressing the previously correct lever. After mastery of the two-link chain, the response chain length was once again increased, and so on until a response chain consisting of six links was completed or until the task timed out. Older children and children with higher IQs mastered longer response chain lengths and were more accurate in performance of this learning task than younger children. In addition, older children and children with higher IQs had higher effective response rates and lower ineffective response rates. No significant effects of the sex of the participant were demonstrated for any of the variables on this task, except overall response rate. The results indicate that this test is sensitive to developmental variables in children, with the degree of sensitivity of certain dependent variables being age-dependent. Characterization of performance of this task by humans facilitates comparisons with animal models employing the same task, thus enhancing its translational utility.     

Retention of autoregulatory control of tubulin synthesis in cytoplasts: demonstration of a cytoplasmic mechanism that regulates the level of tubulin expression

Virtually all animal cells rapidly and specifically depress synthesis of new alpha- and beta-tubulin polypeptides in response to microtubule inhibitors that increase the pool of depolymerized subunits, or in response to direct elevation of the cellular tubulin subunit content through microinjection of exogenous tubulin subunits. Collectively, these previous findings have documented the presence of an apparent eucaryotic, autoregulatory control mechanism that specifies the level of expression of tubulin in cultured animal cells. Mechanistically, this regulation of tubulin synthesis is achieved through modulation of tubulin mRNA levels. To dissect further the molecular pathway that underlies this autoregulatory phenomenon, we have now investigated whether enucleated cells still retain the requisite regulatory machinery with which to alter tubulin synthetic levels in response to fluctuations in the pool size of unpolymerized tubulin subunits. Using two-dimensional gel electrophoresis to analyze the patterns of new polypeptide synthesis, we have determined that such cytoplasts can indeed respond to drug-induced microtubule depolymerization by specific repression of new beta-tubulin synthesis. Moreover, the response of cytoplasts is, if anything, greater in magnitude than that of whole cells. We conclude that autoregulatory control of beta-tubulin gene expression must derive principally, if not exclusively, from a cytoplasmic control mechanism that modulates beta-tubulin mRNA stability. For alpha-tubulin, although the response of cytoplasts after drug-induced microtubule depolymerization is quantitatively less dramatic than that of whole cells, at least part of the regulatory machinery must also be activated through a cytoplasmic regulatory event.