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PubMed2005

Treatment of glomerulonephritis: will we ever have options other than steroids and cytotoxics?

Glomerulonephritis refers to a collection of primary renal disorders and those secondary to a systemic disease, all characterized by inflammation within the glomerulus. Given the underlying immunologic nature of these disorders, they are routinely treated with corticosteriods and various cytotoxic agents. Although in many instances such therapies are successful, they are associated with significant morbidity; as such, alternatives are clearly necessary. Our understanding of the pathogenesis of immunologic glomerular diseases has grown remarkably, in large part from the study of rodent disease models. Fundamental to each disorder is the development of an antigen-specific immune response followed by the effector stage of inflammation. To block the immune response, antigen-specific therapy can be used to induce tolerance, such as through the use of double-stranded DNA molecules in lupus nephritis. Since other antigen systems are less well characterized, inducing a more generalized impairment in the immune response by blocking costimulatory molecules CD40-CD154 and CD28-CD80/86 is a growing approach to treat various immunologic disorders and transplantation. To reduce glomerular inflammation, a variety of effector systems have been targeted, including complement, cytokines/chemokines, adhesion molecules, and mediators of cellular proliferation. Of these, antibodies targeting C5 in the complement system, and antibody and receptor antagonists of tumor necrosis factor-alpha (TNF-alpha) have already been used in glomerular disorders with some promise. Less specific blockade of receptor-mediated events stimulated by platelet-derived growth factors and cell cycle proteins may soon be applied to glomerulonephritis. Finally, interruption of fibrosing pathways, which lead to glomerulosclerosis and interstitial fibrosis common to the end-stage of all glomerulonephritis, is the subject of intense effort which may yield effective biologic therapies. In spite of all these advances, we still are dependent on steroids and cytotoxics to treat glomerulonephritis. To get past this, we must devote significant resources to take observations made in basic research laboratories to develop therapeutics and prove their utility in human disease.

Adrenal Cortex Hormones↗
PubMed2002

Characterization of a major modifier locus for polycystic kidney disease (Modpkdr1) in the Han:SPRD(cy/+) rat in a region conserved with a mouse modifier locus for Alport syndrome.

The genetic analysis of rodent disease models provides a powerful tool to investigate how modifier loci cause variation in the phenotypic expression of a disease. In order to test the existence of modifier loci influencing polycystic kidney disease (PKD) phenotypes, we derived a backcross between PKD susceptible Han:SPRD(cy/+) and control Brown Norway (BN) rats, and performed a whole-genome scan in 182 PKD affected hybrids showing different grades of disease severity. The genetic dissection of PKD in the cross allowed us to detect a modifier locus, Modpkdr1, on rat chromosome 8 that controls PKD severity, kidney mass and plasma urea concentration. Results from database searches and computational analyses demonstrated that the Modpkdr1 locus shows strong evidence of synteny conservation with human and mouse chromosomal regions controlling kidney diseases, including disease progression of Alport syndrome. Comparative genome mapping also provided an inventory of potential candidate genes for modifier(s) of PKD. Analyses of the coding regions for four strong candidates (Ctsh, Bcl2a1, Trpc1 and Slc21a2) in (cy/+), BN and Lewis rat strains did not reveal sequence variants that could be associated with PKD. The characterization of Modpkdr1 may provide new insights into modulating mechanisms involved in the pathogenesis of PKD that could delay disease progression in humans. It may also have strong implications in the identification of pathophysiological factors common to different renal disorders.

Animals↗
PubMed1987

The many causes of meningitis.

Meningitis should be suspected in a patient who presents with fever, meningism, or severe headache. A careful physical examination should be performed of perimeningeal foci, with emphasis on the sinuses, ears, throat, neck, and lungs. A history of exposure to tuberculosis, viral disease, rodents, or suspicious dairy products or farm animals may give clues to the source of the meningitis. Immunosuppression through the use of corticosteroids or chemotherapy for such conditions as Hodgkin's disease, lymphoma, leukemia, malnutrition, or acquired immunodeficiency syndrome (AIDS) should also be noted and alert the clinician to the possible presence of an unusual pathogen. Meningitis associated with leukemia or most of the non-T-cell lymphomas is likely to be from a common bacterial agent (often Listeria), unless the patient is being treated with a steroid or is receiving other chemotherapy. Patients with Hodgkin's disease or AIDS or who have been treated with a steroid are more likely to have cryptococcal or tuberculous meningitis. Neonates and the very elderly may present with only irritability or lethargy and fever, without any of the other common symptoms. In neonates up to one week of age, group B streptococcal infection should be suspected. Gram-negative organisms should be suspected in elderly patients and those who have had neurosurgery. In patients with CSF shunts, infection with coagulase-negative Staphylococcus should be assumed and these patients are treated empirically until results of cultures are received. Several noninfectious conditions may mimic infectious meningitis, as may some unusual causes of infectious meningitis (eg, syphilis and schistosomiasis), which have not been discussed in this article.

Anti-Bacterial Agents↗
PubMedDate not supplied

Analgesic nephropathy in rodents.

While it is clear that humans suffer from "classic" analgesic nephropathy, the causative agents and mechanisms are still not known. A review of the literature revealed that chronic acetaminophen exposure does not produce renal papillary necrosis in rodents or humans. In contrast, while chronic aspirin exposure to rodents results in renal papillary necrosis with renal morphological and functional changes similar to that described in humans, epidemiological studies do not implicate aspirin alone in human analgesic nephropathy. The difference in the effects of aspirin in humans and rats may be due to the inability of epidemiological studies to detect aspirin-induced analgesic nephropathy or more likely to the fact that species differences exist, with the rat being more sensitive than humans. With respect to combinations of aspirin and acetaminophen, with or without caffeine, there are minimal tightly controlled studies. In addition, there is little evidence of enhanced renal papillary necrosis in rodents treated with aspirin and acetaminophen combinations. In summary, it remains to be determined what chemical entities cause "classic" analgesic nephropathy in humans and the mechanisms of this toxicity such that preventative measures can be instituted. Elucidation of the mechanisms of analgesic nephropathy has been hampered due to the lack of animal models that closely mimic the human disease. Rodents do not appear to be an appropriate model.

Acetaminophen↗
PubMed2005

Novel non-rodent models of kidney disease.

Kidney disease in the 21(st) century affects increasing numbers of individuals. We continue to be challenged by our lack of understanding of the pathophysiology of acute and chronic renal disease including genetic diseases involving the kidney. Rodent knockout animals or inbred strains have greatly contributed to our understanding of many monogenetic and complex diseases. Non-rodent animal models of disease have become more attractive since genomic data has become available for a variety of organisms that offer distinct advantages over mice and rats for ease in conducting high-throughput chemical or mutagenesis screens. It is thus timely to examine the physiology and pathophysiology of the kidney or kidney equivalents in these organisms to evaluate their relevance as models for human disease. In addition to organisms whose small size and accessibility facilitate large scale screening approaches, larger animals at the other end of the spectrum offer unique physiological advantages in both size equivalency to humans as well as, in some cases, physiological and pathophysiological responses that closely mimic those of humans. Here we review a selected number of non-rodent experimental models of kidney diseases, focusing on recent advances in the use of the worm Caenorhabditis elegans, the fruitfly Drosophila melanogaster, the zebrafish Danio rerio, the little skate Leucoraja erinacea, the MGH miniature swine, merino cross sheep, and the cow Bos taurus to study kidney disease.

Acute Kidney Injury↗
PubMed2002

Plasmodium yoelii uses the murine Duffy antigen receptor for chemokines as a receptor for normocyte invasion and an alternative receptor for reticulocyte invasion.

Erythrocyte invasion by malaria parasites is a complex multistep process involving parasite and erythrocyte receptors. It is a critical stage in the parasite life cycle and, therefore, a logical step in which to intervene to prevent or ameliorate disease. Rodent models of malaria, commonly Plasmodium yoelii, are frequently used for studies of malaria pathogenesis. Little is known, however, about the invasion machinery of rodent malaria parasites. We have found previously that mice congenic for a region of chromosome 1, containing the Duffy antigen/receptor for chemokines (DARC), have different susceptibility to P yoelii infection. Because P vivax, a human parasite, and P knowlesi, a simian parasite, use DARC to enter human erythrocytes, we sought to identify the role of the murine DARC in P yoelii invasion. Using a novel in vivo invasion assay and DARC knock-out mice, we found that DARC knock-out normocytes (mature erythrocytes) had negligible levels of P yoelii invasion compared with wild-type normocytes, demonstrating that DARC is a receptor for invasion of murine erythrocytes. In contrast, DARC knock-out reticulocytes were invaded at a rate similar to that for wild-type reticulocytes. We conclude that there is a DARC- independent pathway for reticulocyte invasion. These findings represent the first identification of a murine malaria receptor on erythrocytes and the first determination that different pathways of invasion exist on normocytes and reticulocytes. Because we show conservation of host-receptor interactions between rodent and human malaria, we can now use this model to identify how immunity can interfere with the invasion process.

Animals↗
PubMed2002

Ex vivo blockade of endothelin-1 inhibits graft coronary artery disease in a rodent cardiac allograft model.

BACKGROUND: Graft coronary artery disease (GCAD) is characterized by vascular narrowing resulting from intimal hyperplasia. Endothelin (ET)-1, derived from the vascular endothelium and macrophages, stimulates vascular smooth muscle cells (SMCs), which leads to neointimal formation in donor graft coronary arteries. In this study, we hypothesized that antisense (AS) oligodeoxynucleotides (ODN) for preproendothelin-1 (ppET-1) delivered to rat cardiac allografts by means of hyperbaric pressure would reduce the incidence of GCAD. METHODS: PVG donor hearts were infused with ppET-1 AS ODN (80 micromol/liter), sense ODN, scrambled ODN or saline alone and incubated in a pressure chamber at 75 psi or ambient pressure for 45 minutes. Cardiac allografts were heterotopically transplanted into ACI rats treated with cyclosporine (7.5 mg/kg, Days 0 to 9). Allografts were procured at post-operative days (POD) 7 or 90. Reverse transcription-polymerase chain reaction (RT-PCR) assay for ET-1 mRNA and ET01 immunohistochemistry (IHC) were performed at PODs 7 and 90. Elastic staining and IHC with anti-macrophage and alpha-SMC actin antibodies were performed to assess GCAD at POD 90. RESULTS: Treatment with AS ODN and pressure significantly reduced ET-1 mRNA and protein expression. A significant reduction in GCAD was achieved with inhibition of ET-1 and was associated with attenuation of macrophages and SMCs in the neointima. CONCLUSION: Peri-operative ex vivo inhibition of ET-1 expression results in a reduction of GCAD. This highly targeted therapy may be a clinically viable strategy for the prevention of ET-1-induced GCAD following cardiac transplantation.

Animals↗
PubMed1979

Enterovirus 71 isolated from cases of epidemic poliomyelitis-like disease in Bulgaria.

Virological and serological studies of an epidemic disease in Bulgaria, 1975, were carried out. Epidemiologically, clinically and pathomorphologically, the disease simulated almost all known forms of poliomyelitis, acute stem encephalitis, encephalomyocarditis and aseptic meningitis. The studies completely rules out the participation of polioviruses and provided comprehensive evidence for the etiological role of a peculiar enterovirus subsequently identified as enterovirus (EV) type 71 known in the literature since 1974. Altogether, in 1975 and 1976 from 65 cases of poliomyelitis-like disease (PLD) 92 strains of EV71 were isolated, including 37 strains from the brain and medulla, 1 from the cerebrospinal fluid, 10 from mesenterial lymph nodes and tonsils and 44 from faeces. In addition, in 282 convalescent cases of the disease, diagnostic seroconversion or high titers of antibody to this virus were demonstrated. The most successful virus isolation was achieved by inoculation of green monkey kidney cell cultures and newborn white mice. Bulgarian strains of enterovirus 71 regularly caused paralysis in monkeys and morphological poliomyelitis-like lesions in their CNS, and paralysis and myositis with Zenker necrosis in newborn white mice, cotton rats, Syrian hamsters, and 3-week-old cotton rats. The diseased rodents had much more virus in their mucles than in brains.

Adult↗
PubMed2002

Environmental dioxins and endometriosis.

Endometriosis is a common gynecologic problem of unknown etiology. Estrogen dependence and immune modulation are established features of this disease and recently environmental contaminants have been suggested to play a role in the pathobiology of endometriosis as well. Previous work in nonhuman primates has shown that exposure to the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with an increased prevalence and severity of endometriosis. Further animal experiments have implicated dioxin and dioxin-like compounds in this disease. Rodent studies support the plausibility for a role of environmental contaminants in the pathophysiology of endometriosis although a convincing mechanistic hypothesis has yet to be advanced. Small hospital-based case-control studies have failed to provide compelling evidence for or against an association of environmental contaminants and endometriosis. Herein we review the available literature that provides evidence that dioxin and dioxin-like compounds are potent modulators of immune and endocrine function critical to the pathobiology of endometriosis. Furthermore, perspectives on the potential mechanism(s) of dioxin and dioxin-like compound-induced toxicity in endometriosis, important knowledge needs, potential animal models for endometriosis studies, and considerations integral to future human case-control studies are discussed.

Animals↗
PubMedDate not supplied

A new epidemic focus of zoonotic cutaneous leishmaniasis in central Iran.

BACKGROUND: Reports from the health center of Yazd province of increasing cutaneous leishmaniasis (CL) cases led us to carry out an epidemiological study using standard techniques in Ardakan County, central Iran, during 2001. PATIENTS AND METHODS: Data was collected on the prevalence of scars and ulcers over a period of 14 months among 621 households in three villages around Ardakan County. Smears were prepared by scraping the edges of the ulcers. We collected the same data on all school children aged 7 to 11 years old in the area. To determine the reservoir host of the disease, rodents and dogs were caught and examined. Sandflies were collected biweekly from indoor and outdoor locations in the study area, and then identified. Parasites isolated from human and rodents were characterized by RAPD-PCR technique. RESULTS: The prevalence of scars and ulcers were 30.4% and 24.6%, respectively, in 3024 individuals in the three villages. Individuals 10 to 14 years of age were the most highly infected age group, with a rate of 28.4%. Males and females were equally infected. Examination of 892 students in primary schools showed a rate of 22.9% for scars and 23.7% for ulcers. Meriones libycus (42.2%) and Rhombomys opimus (57.8%) were present around the villages. Both were infected with Leishmania. Three of 19 M. libycus (15.7%) and 3 out of 26 R. opimus (11.5%) had positive results. The active season of sandflies was late April to late November. Phlebotomus papatasi and Sergentomyia sintoni were the dominant species indoors and outdoors. Natural leptomonad infection was found in P. caucasicus and S. sintoni from gerbil and Jird burrows. CONCLUSION: Based on this survey, there is an epidemic of zoonotic CL in the area, with Leishmania major as the agent, M. libycus and R. opimus as the reservoir hosts, and most probably Phlebotomus papatasi as the vector because about 77% of indoor sandflies were of this species.

Adolescent↗
PubMed2006

Parkinson's disease: a rethink of rodent models.

Parkinson's disease (PD) is a multifactorial disease with a complex etiology that results from genetic risk factors, environmental exposures and most likely a combination of both. Rodent models of parkinsonism aim to reproduce key pathogenic features of the syndrome including movement disorder induced by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by the formation of alpha-synuclein containing Lewy body inclusions. Despite the creation of many excellent models, both chemically induced and genetically engineered, there is none that accurately demonstrates these features. Recent pathological staging studies in man have also emphasized the significant non-CNS component of PD that has yet to be tackled. Herein, we summarize rodent models of PD and what they offer to the field, and suggest future challenges and opportunities.

Animals↗
PubMed1991

Host associations and seasonal abundance of immature Ixodes persulcatus (Acari: Ixodidae) in a Lyme-disease-endemic area in China.

Ticks of nine small mammal species were studied in an area of endemic Lyme disease in Hailin County, Heilongjiang Province, from 1 May to 10 October 1986. The bulk (93%) total small mammal captures were Apodemus speciosus (45%), Clethrionomys rufocanus (31%), A. agrarius (11%) and Eutamias sibiricus; (5%): these host species accounted for 97% of the 162 ticks collected. Ixodes persulcatus Schulze were most abundant on E. sibiricus (0.64 larvae and 0.08 nymphs/squirrel), and less abundant on A. agrarius (1.16 larvae/mouse), A. speciosus (0.38 larvae/mouse) and C. rufocanus (0.37 larvae and nymphs/vole). The seasonal abundance pattern of larval I. persulcatus on four small mammal species appears as a bimodal peak (June and September), but nymphal I. persulcatus has a monomodal peak during spring. The prevalence of immature I. persulcatus on four small mammal species may play an important role in the epidemiology of Lyme disease in Hailin County.

Animals↗