Neurogenesis in Neurotoxin-induced Animal Models for Parkinson's Disease-A Review of the Current Status

Animal models for Parkinson's disease (PD) are essential for understanding its pathogenesis and for development and testing of new therapies. Discoveries of endogenous neurogenesis in the adult mammalian brain give new insight into the cell-based approach for treatment of neurodegenerative disorders, such as PD. Although a great deal of interest has been focused on endogenous neurogenesis in neurotoxin-induced animal models for PD, it still remains controversial whether neural stem cells migrate into the injured area and contribute to repopulation of depleted dopaminergic neurons in neurotoxin-injured adult brains. The purpose of this review is to examine the data available regarding neurogenesis in neurotoxin-induced animal models of PD. It is hoped that data from the animal investigations available in the literature will promote understanding of the neurotoxin-induced animal models for PD.     

转基因疾病动物模型的研究进展

人类疾病动物模型(animalmodelsofhumandiseases)是为阐明人类疾病的发生机制或建立治疗方法而制作的、具有人类疾病模拟表现的实验动物。疾病动物模型对医学发展做出了很大贡献。但是,许多疾病难以用人工诱发的方法制造动物模型,或许多疾病在实验动物身上不发生或仅仅是高等哺乳类动物才发生,因此难以通过自发或人工定向培育的方法获得动物模型。转基因技术的出现,为人类精确地研究基因与疾病的相关关系提供了可能,而且可以在个体发生的每个阶段中使用任何个体进行遗传功能的分析。因此,转基因疾病动物模型的开发成为转基因动物的热点。文章就转基因疾病动物模型的建立制作及应用前景做一综述。     

Copper-induced hepatitis: the COMMD1 deficient dog as a translational animal model for human chronic hepatitis

Chronic inflammatory liver disease regardless of aetiology leads to failing regeneration and fibrosis, ending in cirrhosis. Both in man and in animals this worldwide health problem has no definitive cure. Chronic liver injury causes hepatic stellate cells to proliferate and differentiate into matrix-producing cells. New therapeutic options will be developed upon detailed understanding of the molecular mechanisms driving liver fibrosis. This may lead to new anti-fibrotic therapies which need to be tested in suitable models before application in the veterinary and human clinic. On the other side, to restore the failing regenerative capacity of the diseased liver cells, adult progenitor cells are of interest, as an alternative to whole organ transplantation. In order to find the most suitable large animal model it is important to recognise that the typical histopathological reaction pattern of the liver can differ between mammalian species. It is therefore imperative that specialists in veterinary internal medicine and pathology, being familiar with the diseases and pathologies of the liver in different animal species, are teaming-up in finding the best models for veterinary and human liver diseases. Several large animal models have been mentioned, like pigs, sheep, and dogs. Based on the observations that man and dog share the same hepatopathies and have identical clinical, pathological and pathogenetic reaction patterns during the development of liver disease, the dog seems to be a properly suited species to test new therapeutic strategies for pets and their best friends.     

Crimean–Congo haemorrhagic fever virus: Past,present and future insights for animal modelling and medical countermeasures

Crimean–Congo haemorrhagic fever (CCHF) is a widespread tick‐borne viral zoonosis with a case‐fatality rate ranging from 9% to 50% in humans. Although a licensed vaccine to prevent infection by the CCHF virus (CCHFV) exists, its ability to induce neutralizing antibodies is limited and its efficacy against CCHFV remains undetermined. In addition, controlling CCHF infections by eradication of the tick reservoir has been ineffective, both economically and logistically, and the treatment options for CCHF remain limited. In this review, we first critically discuss the existing animal models to evaluate therapeutics for CCHF. We then review the therapeutic options for CCHF that have been investigated in human cases, followed by investigational drugs that have been evaluated in pre‐clinical studies. We highlight the importance of understanding human prognostic factors in developing an animal model for CCHF that recapitulates hallmarks of human disease and its implication for selecting therapeutic candidates.     

Genetic alterations in thyroid cancer: the role of mouse models

Thyroid carcinomas are the most common endocrine neoplasms in humans, with a globally increasing incidence. Thyroid follicular cells and neuroendocrine (parafollicular) C cells are each susceptible to neoplastic transformation, resulting in thyroid cancers of differing phenotypes with unique associated genetic mutations and clinical outcomes. Over the past 15 years, several sophisticated genetically engineered mouse models of thyroid cancer have been created to further our understanding of the genetic events leading to thyroid carcinogenesis in vivo. The most significant mouse models of papillary, follicular, anaplastic, and medullary thyroid carcinoma are highlighted, with particular emphasis on the relationship between the relevant oncogenes in these models and genetic events in the naturally occurring human disease. Limitations of each model are presented, and the need for additional models to better recapitulate certain aspects of the human disease is discussed.     

The role of tissue factor and tissue factor pathway inhibitor in health and disease states

Objective – To review the veterinary and human literature on the role of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in health and disease states.
Data Sources – Original research articles and scientific reviews from both human and veterinary literature were searched for relevance to TF and TFPI.
Human Data Synthesis – Interest in both TF and TFPI has grown widely over the last several years. The impact TF plays in coagulation, inflammation, angiogenesis, tumor metastasis, and cellular signaling has become apparent. Treatment with TFPI for severe sepsis has been examined and is still currently under investigation. Inhibition of the TF pathway is being studied as an aid in the treatment of neoplasia. The important physiologic and pathophysiologic role these molecules play has only begun to be understood.
Veterinary Data Synthesis – There is a paucity of publications that discuss the importance of TF and TFPI in veterinary medicine. An enhanced understanding of the TF pathway in human medicine, in experimental animal models treating sepsis with TFPI, and in animal models demonstrating the proangiogenic properties of TF provides relevance to veterinary medicine.
Conclusion – It is apparent that TF and TFPI are important in health and disease. An enhanced understanding of the physiologic and pathophysiologic roles of these factors provides better insight into coagulation, inflammation, angiogenesis, disseminated intravascular coagulation, and tumor metastasis. This greater understanding may provide for the development of therapeutics for sepsis, disseminated intravascular coagulation, and neoplasia.     

Basic research on BSE transmission to people

Prion diseases of animal and man belong to neurological diseases with amyloidal deposition of the respective proteins. As to prion disease, the cellular prionprotein is in its abnormal isoform(s) an essential component of prionprotein aggregates found in affected tissue. In contrast to all neurodegenerative diseases like Morbus Alzheimer or Huntington's disease, prion diseases are transmissible. Therefore, prion diseases were designated Transmissible Spongiform Encephalopathies (TSE). The diseases are well known since decades. Scrapie was first described around 1750, a BSE case was reported in the 1850, most likely a misdiagnosis, and in 1920/1930 the human Creutzfeldt-Jakob disease (CJD) had been described. Transmission of CJD i.e. Kuru had been suspected in the early 1950s and erronously classified as slow virus disease. The CJD transmission posed a problem to humans when transplants from CJD cases were used for treatment. Fortunately, these iatrogenic transmissions remained limited. But with the advent of BSE and appearance of variant CJD cases in the UK and some places in Europe scientists suspected that transmission from cattle to man could have happened. From animal models we know of successful transmission via several routes. Species barriers do not completely prevent transmission. Rather transmission barriers might exist controlling individual susceptibility against prions. Modes of transmission, susceptibility for transmission, identification of receptor molecules as well as molecular mechanisms of the transmission process are intensely investigated. Current knowledge let us to assume that inapparent stages of prion infection pretend a (not existing) species barrier. This inapparent infection preceeds overt disease and, thus, most re-search focuses on the development of highly sensitive assay systems for detection of minute amounts of pathological prionprotein in suspected cases. Inapparence also should warn us to underestimate BSE or human vCJD cases; at present, 124 in Europe and one probable case in Hongkong (7 March 2002). Whether BSE had spread to other parts of the world by animal nutrition components or meat can neither be excluded nor confirmed at this time. New data on transmission and consequences of BSE for the human population are summarized in this review.     

类胡萝卜素β-隐黄质结构组成及生物功能概述

β-隐黄质具有抗氧化防御功能和细胞间通讯的功能,在生物体内β-隐黄质最重要的功能是合成VA的前体。在体外动物模型和人体研究中表明,来源于食物中的β-隐黄质,相比α-胡萝卜素和β-胡萝卜素,具有更好的生物利用率。近年来,国内外学者对β-胡萝卜素研究较多,而对β-隐黄质的相关报道较少。对类胡萝卜素β-隐黄质结构组成及生物功能进行了概述,旨在为全面了解类胡萝卜素提供参考。     

Hypoxic Ischemic Encephalopathy—What Can We Learn from Humans?

Hypoxic ischemic encephalopathy (HIE) is a condition that occurs in both human newborns and foals. The condition is the subject of extensive current research in human infants, but there have been no direct studies of HIE in foals, and hence, knowledge of the condition has been extrapolated from studies in humans and other animal models. The purpose of this review article is to highlight the most up-to-date and relevant research in the human field, and discuss how this potentially might have an impact in the management of foals with HIE.     

Genetics and disease resistance

Genetic components of disease resistance have been described in most of important diseases in human as well as in laboratory and livestock animals. However the basic mechanisms have been established in a few examples only. The reasons herefore are the mostly polygenic inheritance of disease resistance traits, the missing of suitable animal models and the dominance of environmental effects like infection pressure, immune status, and stressors, limiting the view on responsible gene variants. Ethical and practical aspects may further hinder research on disease resistance in certain species. Livestock animals play a crucial role in disease resistance research, because of distinct genetic diversity within and between breeds, because of an often distinct metabolic congruency with humans, and aiming towards the improvement of hygiene and economy of production and animal welfare. The following sections will review disease resistance in livestock animals and their practical implications, completed by examples of our own research activities.     

Hyperbaric oxygen therapy. Part 1: history and principles

Objective – Review the historical development and physiologic principles of hyperbaric oxygen therapy (HBOT) based on human and veterinary experimental literature and current equipment in use. Data Sources – Review of basic physiologic concepts. Data from human and veterinary journals were reviewed through Pubmed and Veterinary Information Network database searches as well as reference searches on several articles covering hyperbaric therapy in clinically applicable situations. Human Data Synthesis – HBOT has been gaining acceptance as an adjunctive treatment in human medicine. The understanding of the physiology and application of hyperbaric therapy is increasing through ongoing research and greater access to hyperbaric equipment. Veterinary Data Synthesis – Several animal models have been utilized to examine the effects of HBOT. Most models utilize dogs and rats but pigs, cats, and other species have been studied. Conclusions – Hyperbaric therapy utilizes several physiologic principles of how gases respond under pressure and more specifically of how oxygen responds under pressure. The increase in concentration of oxygen in solution, based on its solubility under pressure, increases the diffusion gradient for its delivery deeper into tissues, which is the premise of HBOT. Ultimately the increases in dissolved oxygen generated by hyperbaric therapy have several physiologic effects that can alter tissue responses to disease and injury. As this technology becomes more available to clinical practice, HBOT should be considered as a therapeutic option.     

The pathogenesis and pathology of bovine tuberculosis with insights from studies of tuberculosis in humans and laboratory animal models

This paper reviews key insights the discipline of pathology has contributed to our understanding of bovine tuberculosis in the context of findings of studies of tuberculosis in humans and laboratory animal models. Analysis and extrapolation of data from other species have the potential to expand our understanding of the pathogenesis of the disease in cattle. The distribution of lesions in affected cattle, humans and laboratory animals illustrate the primacy of the respiratory tract as portal of infection and raise questions about the role of the upper respiratory tract surface, tonsil and dorsal lung regions in disease pathogenesis and transmission. The mechanisms behind significant pathological processes such as necrosis, apoptosis and liquefaction, occurring within lesions, are explored and their potential practical significance assessed in the context of herd disease dynamics and vaccine development. It is proposed that effective 'innate' host defences result in many animals and humans remaining disease-free and tuberculin test negative following exposure to infection. Furthermore, the concepts of latency and disease reactivation, considered significant factors in perpetuating tuberculosis in human populations, are explored in the context of the bovine disease.     

Oral examination results in rescued ferrets: clinical findings

Ferrets have increased in popularity as pets, and a growing number are seen in companion animal practice. Domestic ferrets are commonly used as animal models for research of human oral conditions. The present study evaluated the prevalence of oral pathology in rescued ferrets which - to the authors' knowledge - has not yet been described in the scientific literature. Conscious oral examination was performed on 63 ferrets, of which 49 underwent general anesthesia for further examination. The most common clinical findings included malocclusion of mandibular second incisor teeth (95.2%); extrusion of canine teeth (93.7%); and abrasion and attrition of teeth (76.2%). Tooth fractures were exclusively associated with canine teeth and found in 31.7% of ferrets. Pulp exposure was confirmed in 60.0% of fractured teeth. The normal gingival sulcus depth measured < 0.5-mm in 87.8% of anesthetized ferrets. Clinical evidence of periodontal disease was present in 65.3% of anesthetized ferrets (gingivitis or probing depths > 0.5-mm), however advanced periodontal disease (i.e. periodontal pockets > 2-mm or stage 3 furcation exposure) was not found upon clinical examination. There was no evidence of tooth resorption, dental caries, stomatitis, or oral tumors in the examined group of ferrets.     

Developing stochastic epidemiological models to quantify the dynamics of infectious diseases in domestic livestock

A stochastic model describing disease transmission dynamics for a microparasitic infection in a structured domestic animal population is developed and applied to hypothetical epidemics on a pig farm. Rational decision making regarding appropriate control strategies for infectious diseases in domestic livestock requires an understanding of the disease dynamics and risk profiles for different groups of animals. This is best achieved by means of stochastic epidemic models. Methodologies are presented for 1) estimating the probability of an epidemic, given the presence of an infected animal, whether this epidemic is major (requires intervention) or minor (dies out without intervention), and how the location of the infected animal on the farm influences the epidemic probabilities; 2) estimating the basic reproductive ratio, R0 (i.e., the expected number of secondary cases on the introduction of a single infected animal) and the variability of the estimate of this parameter; and 3) estimating the total proportion of animals infected during an epidemic and the total proportion infected at any point in time. The model can be used for assessing impact of altering farm structure on disease dynamics, as well as disease control strategies, including altering farm structure, vaccination, culling, and genetic selection.     

Mechanisms of resistance and susceptibility to experimental visceral leishmaniosis: BALB/c mouse versus syrian hamster model

ABSTRACT: Several animal models have been established to study visceral leishmaniosis (VL), a worldwide vector-borne disease affecting humans and domestic animals that constitutes a serious public health problem. BALB/c mice and Syrian hamsters are the most widely used experimental models. In this paper, we summarize the advantages and disadvantages of these two experimental models and discuss the results obtained using these models in different studies of VL. Studies using the BALB/c mouse model have underscored differences between the liver and spleen in the course of VL, indicating that pathological evaluation of the visceral organs is essential for understanding the immune mechanisms induced by Leishmania infantum infection. The main goal of this review is to collate the relevant literature on Leishmania pathogenesis into a sequence of events, providing a schematic view of the main components of adaptive and innate immunity in the liver and spleen after experimental infection with L. infantum or L. donovani. This review also presents several viewpoints and reflections about some controversial aspects of Leishmania research, including the choice of experimental model, route of administration, inoculum size and the relevance of pathology (intimately linked to parasite persistence): a thorough understanding of which is essential for future VL research and the successful development of efficient control strategies for Leishmania spp.     

The use of antibiotics on small dairy farms in rural Peru

Very little is known about the use of antibiotics on small dairy farms in lower/middle-income countries. The use of these drugs can have profound impacts on animal health, farmer income and public health. A survey of 156 farmers was conducted in Cajamarca, a major dairy-producing center in the highlands of Peru characterized by small farms (<15 cows) to assess patterns and determinants of antibiotic use and farmers’ knowledge of antibiotics. The reported incidence of disease on these farms was relatively low (0.571 episodes of disease per cow-year), but more than 83% of the reported episodes were treated with antibiotics. The most commonly used antibiotics were oxytetracycline, penicillin and trimethoprim-sulfamethoxazole drugs; antiparasitic drugs were also used to treat what were likely bacterial infections. An increased incidence of treated disease was significantly associated with smaller farm size, lower farmer income, the previous use of the Californian Mastitis test on the farm and antibiotic knowledge. Farmers’ knowledge of antibiotics was assessed with a series of questions on antibiotics, resulting in a “knowledge score”. Increased knowledge was significantly associated with the use of antibiotics for preventative reasons, the purchase of antibiotics from feed-stores, the experience of complications in animals after having administered antibiotics, the number of workers on the farm and the educational level of the farmer. Overall, antibiotics appeared to be used infrequently, most likely because therapeutic interventions were sought only when the animal had reached an advanced stage of clinical disease. Few farmers were able to define an antibiotic, but many farmers understood that the use of antibiotics carried inherent risks to their animals and potentially to the consumers of dairy products from treated animals. The results of this study are useful for understanding the patterns of antibiotic use and associated management, demographic and knowledge factors of farmers on small dairy farms in rural Peru.     

PK-PD integration and PK-PD modelling of nonsteroidal anti-inflammatory drugs: principles and applications in veterinary pharmacology

Much useful information relevant to elucidation of mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) at the molecular level can be obtained from integrating pharmacokinetic (PK) and pharmacodynamic (PD) data, such data being obtained usually, although not necessarily, in separate studies. Integrating PK and PD data can also provide a basis for selecting clinically relevant dosing schedules for subsequent evaluation in disease models and clinical trials. The principles underlying and uses of PK-PD integration are illustrated in this review for phenylbutazone in the horse and cow, carprofen and meloxicam in the horse, carprofen and meloxicam in the cat and nimesulide in the dog. In the PK-PD modelling approach for NSAIDs, the PK and PD data are generated (usually though not necessarily) in vivo in the same investigation and then modelled in silico, usually using the integrated effect compartment or indirect response models. Drug effect is classically modelled with the sigmoidal E(max) (Hill) equation to derive PD parameters which define efficacy, potency and sensitivity. The PK-PD modelling approach for NSAIDs can be undertaken at the molecular level using surrogates of inhibition of cyclooxygenase (COX) isoforms (or indeed other enzymes e.g. 5-lipoxygenase). Examples are provided of the generation of PD parameters for several NSAIDs (carprofen, ketoprofen, vedaprofen, flunixin and tolfenamic acid) in species of veterinary interest (horse, calf, sheep and goat), which indicate that all drugs investigated except vedaprofen were non-selective for COX-1 and COX-2 in the four species investigated under the experimental conditions used, vedaprofen being a COX-1 selective NSAID. In these studies, plasma concentration was linked to COX inhibitory action in the biophase using an effect compartment model. Data for S-(+)-ketoprofen have been additionally subjected to inter-species modelling and allometric scaling of both PK and PD parameters. For several species values of four PK parameters were highly correlated with body weight, whilst values for PD parameters based on COX inhibition lacked allometric relationship with body weight. PK-PD modelling of NSAIDs has also been undertaken using clinical end-points and surrogates for clinical end-points in disease models. By measurement of clinically relevant indices in clinically relevant models, data generated for PD parameters have been used to set dosages and dose intervals for evaluation and confirmation in clinical trials. PK-PD modelling of NSAIDs is likely to prove superior to conventional dose titration studies for dosage schedule determination, as it sweeps the whole of the concentration-effect relationship for all animals and therefore permits determination of genuine PD parameters. It also introduces time as a second independent variable thus allowing prediction of dosage interval. Using indirect response models and clinically relevant indices, PD data have been determined for flunixin, phenylbutazone and meloxicam in the horse, nimesulide in the dog and meloxicam in the cat.     

Domestic animal models for biomedical research

Experimental animals in biomedical research provide insights into disease mechanisms and models for determining the efficacy and safety of new therapies and for discovery of corresponding biomarkers. Although mouse and rat models are most widely used, observations in these species cannot always be faithfully extrapolated to human patients. Thus, a number of domestic species are additionally used in specific disease areas. This review summarizes the most important applications of domestic animal models and emphasizes the new possibilities genetic tailoring of disease models, specifically in pigs, provides.     

Periodontal therapy

Periodontal disease is the most common disease in small animal patients. It not only creates severe localized infection, but it has been linked to numerous severe systemic maladies. Proper therapy of this disease process results in a significant increase in the overall health of the patient. The treatment of periodontal disease is currently evolving due to the acceptance of the specific plaque hypothesis of periodontal disease. These findings have led to the development of the "one-stage full-mouth disinfection" treatment as well as a vaccine against these organisms. However, the cornerstone of therapy is still meticulous plaque control. This control is achieved via a combination of regular dental prophylaxis and home care. With progressive disease, advanced periodontal surgery or extraction becomes necessary.