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Zhou Y, Feng P, Tian F, Fong H, Yang H, Zhu H. A CT-based radiomics model for predicting lymph node metastasis in hepatic alveolar echinococcosis patients to support lymph node dissection. Eur J Med Res 2024; 29:409. [PMID: 39113113 PMCID: PMC11304587 DOI: 10.1186/s40001-024-01999-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 07/27/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Hepatic alveolar echinococcosis (AE) is a severe zoonotic parasitic disease, and accurate preoperative prediction of lymph node (LN) metastasis in AE patients is crucial for disease management, but it remains an unresolved challenge. The aim of this study was to establish a radiomics model for the preoperative prediction of LN metastasis in hepatic AE patients. METHODS A total of 100 hepatic AE patients who underwent hepatectomy and hepatoduodenal ligament LN dissection at Qinghai Provincial People's Hospital between January 2016 and August 2023 were included in the study. The patients were randomly divided into a training set and a validation set at an 8:2 ratio. Radiomic features were extracted from three-dimensional images of the hepatoduodenal ligament LNs delineated on arterial phase computed tomography (CT) scans of hepatic AE patients. Least absolute shrinkage and selection operator (LASSO) regression was applied for data dimensionality reduction and feature selection. Multivariate logistic regression analysis was performed to develop a prediction model, and the predictive performance of the model was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS A total of 7 radiomics features associated with LN status were selected using LASSO regression. The classification performances of the training set and validation set were consistent, with area under the operating characteristic curve (AUC) values of 0.928 and 0.890, respectively. The model also demonstrated good stability in subsequent validation. CONCLUSION In this study, we established and evaluated a radiomics-based prediction model for LN metastasis in patients with hepatic AE using CT imaging. Our findings may provide a valuable reference for clinicians to determine the occurrence of LN metastasis in hepatic AE patients preoperatively, and help guide the implementation of individualized surgical plans to improve patient prognosis.
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Affiliation(s)
- Yinshu Zhou
- First School of Clinical Medicine, Jinan University, No.601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Pengcai Feng
- General Surgery Department, Qinghai Provincial People's Hospital, Xining, 810000, Qinghai, China
| | - Fengyuan Tian
- General Surgery Department, Qinghai Provincial People's Hospital, Xining, 810000, Qinghai, China
| | - Hin Fong
- First School of Clinical Medicine, Jinan University, No.601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Haoran Yang
- School of Medicine, Jinan University, No.601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Haihong Zhu
- General Surgery Department, Qinghai Provincial People's Hospital, Xining, 810000, Qinghai, China.
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Aimaitijiang Y, Jiang TM, Shao YM, Aji T. Fifty-five cases of hepatic alveolar echinococcosis combined with lymph node metastasis: A retrospective study. World J Gastroenterol 2024; 30:2981-2990. [PMID: 38946870 PMCID: PMC11212701 DOI: 10.3748/wjg.v30.i23.2981] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 05/02/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Lymph node metastasis is a specific type of metastasis in hepatic alveolar echinococcosis (AE). Currently, there is a scarcity of describing the clinical characteristics and lymph node metastasis rules of patients with hepatic AE combined with lymph node metastasis and its mechanism and management are still controversial. Radical hepatectomy combined with regional lymph node dissection is a better treatment. AIM To analyse the clinical features of hepatic AE combined with lymph node metastasis to explore its treatment and efficacy. METHODS A total of 623 patients with hepatic AE admitted to the First Affiliated Hospital of Xinjiang Medical University from 1 January 2012 to 1 January 2022 were retrospectively analysed. Fifty-five patients with combined lymph node metastasis were analysed for their clinical data, diagnosis and treatment methods, follow-up efficacy, and characteristics of lymph node metastasis. Finally, we comparatively analysed the lymph node metastasis rates at different sites. Categorical variables are expressed as frequencies and percentages, and the analysis of difference was performed using the χ 2 test. The Bonferroni method was used for pairwise comparisons when statistical differences existed between multiple categorical variables. RESULTS A lymph node metastasis rate of 8.8% (55/623) was reported in patients with hepatic AE, with a female predilection (69.1%) and a statistically significant sex difference (χ 2 = 8.018, P = 0.005). Of the 55 patients with lymph node metastasis, 72.7% had a parasite lesion, neighbouring organ invasion, and metastasis stage of P3N1M0 and above, of which 67.3%, 78.2%, and 34.5% of hepatic AE lesions invaded the bile ducts, blood vessels, and distant metastases, respectively. Detection rates of lymph node metastasis of 16.4%, 21.7%, and 34.2% were reported for a preoperative abdominal ultrasound, magnetic resonance imaging, and computed tomography examinations. All patients were intraoperatively suspected with enlarged lymph nodes and underwent radical hepatectomy combined with regional lymph node dissection. After surgery, a routine pathological examination was conducted on the resected lymph nodes. A total of 106 positive lymph nodes were detected in six groups at various sites, including 51 single-group metastasis cases and four multi-group metastasis cases. When the metastasis rates at different sites were statistically analysed, we observed that the metastasis rate in the para-hepatoduodenal ligament lymph nodes was significantly higher than that of the other sites (χ 2 = 128.089, P = 0.000 < 0.05). No statistical difference was observed in the metastasis rate between the five other groups. Clavien-Dindo grade IIIa complication occurred in 14 cases, which improved after administering symptomatic treatment. Additionally, lymph node dissection-related complications were not observed. Recurrence after 2 years was observed in one patient. CONCLUSION Lymph node metastasis is a rare form of metastasis in hepatic AE, which is more frequent in women. Para-hepatoduodenal ligament lymph nodes are commonly observed. Radical hepatectomy combined with regional lymph node dissection is a safe, effective, and feasible treatment for liver AE combined with lymph node metastasis.
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Affiliation(s)
- Yilizhati Aimaitijiang
- State Key Laboratory on Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Clinical College, Xinjiang Medical University, Urumqi 830011, Xinjiang Uygur Autonomous Region, China
- The First Ward of Hepatobiliary and Pancreatic Surgery, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi 830011, Xinjiang Uygur Autonomous Region, China
| | - Tie-Min Jiang
- Department of Hepatobiliary & Hydatid Diseases, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang Uygur Autonomous Region, China
| | - Ying-Mei Shao
- Xinjiang Clinical Research Center for Echinococcosis and Hepatobiliary Diseases, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang Uygur Autonomous Region, China
| | - Tuerganaili Aji
- Department of Hepatobiliary & Hydatid Diseases, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang Uygur Autonomous Region, China
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Xu X, Gao C, Qian X, Liu H, Wang Z, Zhou H, Zhou Y, Wang H, Hou L, He S, Feng X, Fan H. Treatment of Complicated Hepatic Alveolar Echinococcosis Disease With Suspicious Lymph Node Remote Metastasis Near the Inferior Vena Cava-Abdominal Aorta: A Case Report and Literature Review. Front Oncol 2022; 12:849047. [PMID: 35402272 PMCID: PMC8987535 DOI: 10.3389/fonc.2022.849047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 02/28/2022] [Indexed: 11/21/2022] Open
Abstract
Echinococcosis is a human-animal parasitic disease caused by Echinococcosis tapeworm larvae in humans. From a global perspective, it is mainly prevalent in the mid-high latitudes of the Northern Hemisphere, and it is a widespread infectious disease. Its form, host and release areas are slightly different. In clinical practice, Echinococcus granulosus (hepatic cystic echinococcosis) is the most common. Its growth mode is swelling growth and its metastasis is more common in implanted metastasis; However, hepatic alveolar echinococcosis (HAE) is rare. It has been reported that HAE can metastasize through the blood or lymph nodes, and its invasive growth pattern is known as “carcinoma”. At this time, it may be accompanied by invasion of the portal vein and inferior vena cava(IVC)or metastasis to distant organs outside the liver (such as lung, brain, lymph nodes). Most patients are in the middle or late stages, making treatment complicated. World Health Organization guidelines recommend radical resection of HAE; However, there is no consensus on lymph node dissection. To date, there have been no reports of cases of HAE accompanied by inferior vena cava-para-abdominal aortic suspected lymph node metastasis and infection. This article reports a clinical case of a complex HAE treated by the surgical method of “middle liver resection + abdominal enlarged lymph node resection + inferior vena cava repair”, and histological examination was performed to illustrate the differences in microscopic pathology of alveolar echinococcosis invading the liver and lymph nodes at different magnifications. This article reviews the relevant literature on HAE and derives the latest treatment methods for HAE to provide a reference for future clinical cases of similar alveolar echinococcosis and maximize the benefits of patients.
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Hemphill A, Rufener R, Ritler D, Dick L, Lundström‐Stadelmann B. Drug Discovery and Development for the Treatment of Echinococcosis, Caused by the Tapeworms
Echinococcus granulosus
and
Echinococcus multilocularis. METHODS AND PRINCIPLES IN MEDICINAL CHEMISTRY 2019:253-287. [DOI: 10.1002/9783527808656.ch10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Lundström-Stadelmann B, Rufener R, Ritler D, Zurbriggen R, Hemphill A. The importance of being parasiticidal… an update on drug development for the treatment of alveolar echinococcosis. Food Waterborne Parasitol 2019; 15:e00040. [PMID: 32095613 PMCID: PMC7034016 DOI: 10.1016/j.fawpar.2019.e00040] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 02/06/2019] [Accepted: 02/12/2019] [Indexed: 02/06/2023] Open
Abstract
The lethal disease alveolar echinococcosis (AE) is caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis. Current chemotherapeutical treatment of AE relies on albendazole and mebendazole, with the caveat that these compounds are not parasiticidal. Drugs have to be taken for a prolonged period of time, often life-long, which can cause adverse effects and reduces the patients' quality of life. In some individuals, benzimidazoles are inactive or cause toxicity, leading to treatment discontinuation. Alternatives to benzimidazoles are urgently needed. Over the recent years, in vivo and in vitro models for low-to-medium throughput drug discovery against AE have been set in place. In vitro drug tests include the phosphoglucose-isomerase (PGI) assay to measure physical damage induced to metacestodes, and viability assays to assess parasiticidal activity against metacestodes and stem cells. In vitro models are also employed for studies on mechanisms of action. In vivo models are thus far based on rodents, mainly mice, and benefits could be gained in future by comparative approaches in naturally infected dogs or captive monkeys. For the identification of novel drugs against AE, a rare disease with a low expected market return, drug-repurposing is the most promising strategy. A variety of chemically synthesized compounds as well as natural products have been analyzed with respect to in vitro and/or in vivo activities against AE. We here review and discuss the most active of these compounds including anti-infective compounds (benzimidazoles, nitazoxanide, amphotericin B, itraconazole, clarithromycin, DB1127, and buparvaquone), the anti-infective anti-malarials (artemisinin, ozonids, mefloquine, and MMV665807) and anti-cancer drugs (isoflavones, 2-methoxyestradiol, methotrexate, navelbine, vincristine, kinase inhibitors, metallo-organic ruthenium complexes, bortezomib, and taxanes). Taking into account the efficacy as well as the potential availability for patients, the most promising candidates are new formulations of benzimidazoles and mefloquine. Future drug-repurposing approaches should also target the energy metabolism of E. multilocularis, in particular the understudied malate dismutation pathway, as this offers an essential target in the parasite, which is not present in mammals.
Benzimidazoles are used to treat AE, but new drugs are needed. New drugs against AE can be identified by drug repurposing. Drugs against other infectious diseases and cancer can be repurposed against AE. Most promising are new formulations of benzimidazoles and mefloquine. Future approaches should include targeting the energy metabolism of the parasite.
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Affiliation(s)
- Britta Lundström-Stadelmann
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland
| | - Reto Rufener
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland
| | - Dominic Ritler
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland
| | - Raphael Zurbriggen
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland
| | - Andrew Hemphill
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland
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Abstract
The biology of Echinococcus, the causative agent of echinococcosis (hydatid disease) is reviewed with emphasis on the developmental biology of the adult and metacestode stages of the parasite. Major advances include determining the origin, structure and functional activities of the laminated layer and its relationship with the germinal layer; and the isolation, in vitro establishment and characterization of the multipotential germinal cells. Future challenges are to identify the mechanisms that provide Echinococcus with its unique developmental plasticity and the nature of activities at the parasite-host interface, particularly in the definitive host. The revised taxonomy of Echinococcus is presented and the solid nomenclature it provides will be essential in understanding the epidemiology of echinococcosis.
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Bacciarini LN, Gottstein B, Pagan O, Rehmann P, Gröne A. Hepatic Alveolar Echinococcosis in Cynomolgus Monkeys (Macaca fascicularis). Vet Pathol 2016; 41:229-34. [PMID: 15133171 DOI: 10.1354/vp.41-3-229] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Alveolar echinococcosis was diagnosed in 12 cynomolgus monkeys ( Macaca fascicularis) at postmortem examination within a period of 6 years. Besides consistent involvement of the liver, parasitic lesions were also present in mesenteric lymph nodes, pancreas, lung, and kidney. In the liver, various patterns of host's responses to parasitic tissue could be distinguished. Infiltration of macrophages, often multinucleated, around usually intact metacestodes was the main feature of one pattern. A second pattern was characterized by the presence of abundant, normally degenerate granulocytes in addition to macrophages surrounding collapsed laminated structures. Finally and as a third pattern, some cysts were surrounded by marked collagen deposition, which was usually not a significant feature of the other foci. Parasitic cysts with protoscolices were observed in foci with the first and third pattern but not in the second one. The simultaneous occurrence of all three patterns was observed in most animals. Type AA amyloid was identified either in the space of Dissé, macro-phages or blood vessel walls in nine animals using immunohistochemistry. Identity of parasitic structures such as metacestodes of Echinococcus multilocularis was confirmed immunohistochemically. All animals that could be tested serologically (7/12) had detectable antibodies against the E. multilocularis-specific Em2 antigen. Liver lesions of six animals were additionally analyzed by polymerase chain reaction, yielding the amplification of a specific E. multilocularis DNA fragment in each case.
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Affiliation(s)
- L N Bacciarini
- Institut für Tierpathologie, Abteilung für Fisch- und Wildtiermedizin, Universität Bern, Switzerland.
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Hemphill A, Stadelmann B, Rufener R, Spiliotis M, Boubaker G, Müller J, Müller N, Gorgas D, Gottstein B. Treatment of echinococcosis: albendazole and mebendazole--what else? ACTA ACUST UNITED AC 2014; 21:70. [PMID: 25526545 PMCID: PMC4271654 DOI: 10.1051/parasite/2014073] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 12/11/2014] [Indexed: 01/14/2023]
Abstract
The search for novel therapeutic options to cure alveolar echinococcosis (AE), due to the metacestode of Echinococcus multilocularis, is ongoing, and these developments could also have a profound impact on the treatment of cystic echinococcosis (CE), caused by the closely related Echinococcus granulosus s.l. Several options are being explored. A viable strategy for the identification of novel chemotherapeutically valuable compounds includes whole-organism drug screening, employing large-scale in vitro metacestode cultures and, upon identification of promising compounds, verification of drug efficacy in small laboratory animals. Clearly, the current focus is targeted towards broad-spectrum anti-parasitic or anti-cancer drugs and compound classes that are already marketed, or that are in development for other applications. The availability of comprehensive Echinococcus genome information and gene expression data, as well as significant progress on the molecular level, has now opened the door for a more targeted drug discovery approach, which allows exploitation of defined pathways and enzymes that are essential for the parasite. In addition, current in vitro and in vivo models that are used to assess drug efficacy should be optimized and complemented by methods that give more detailed information on the host-parasite interactions that occur during drug treatments. The key to success is to identify, target and exploit those parasite molecules that orchestrate activities essential to parasite survival.
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Affiliation(s)
- Andrew Hemphill
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
| | - Britta Stadelmann
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
| | - Reto Rufener
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
| | - Markus Spiliotis
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
| | - Ghalia Boubaker
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
| | - Joachim Müller
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
| | - Norbert Müller
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
| | - Daniela Gorgas
- Department of Clinical Veterinary Medicine, Clinical Radiology, Bremgartenstrasse 109a, 3012 Berne, Switzerland
| | - Bruno Gottstein
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
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Echinococcus as a model system: biology and epidemiology. Int J Parasitol 2014; 44:865-77. [DOI: 10.1016/j.ijpara.2014.07.005] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Revised: 07/19/2014] [Accepted: 07/21/2014] [Indexed: 12/22/2022]
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Echinococcus multilocularis as an experimental model in stem cell research and molecular host-parasite interaction. Parasitology 2009; 137:537-55. [PMID: 19961652 DOI: 10.1017/s0031182009991727] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Totipotent somatic stem cells (neoblasts) are key players in the biology of flatworms and account for their amazing regenerative capability and developmental plasticity. During recent years, considerable progress has been made in elucidating molecular features of neoblasts from free-living flatworms, whereas their role in parasitic species has so far merely been addressed by descriptive studies. Very recently, however, significant advances have been made in the in vitro culture of neoblasts from the cestode Echinococcus multilocularis. The isolated cells proved capable of generating mature metacestode vesicles under laboratory conditions in a manner that closely resembles the oncosphere-metacestode transition during natural infections. Using the established neoblast cultivation protocols, combined with targeted manipulation of Echinococcus genes by RNA-interference, several fundamental questions of host-dependent parasite development can now be addressed. Here, I give an overview of current cultivation techniques for E. multilocularis neoblasts and present experimental approaches to study their function. Furthermore, I introduce the E. multilocularis genome sequencing project that is presently in an advanced stage. The combined input of data from the E. multilocularis sequencing project, stem cell cultivation, and recently initiated attempts to genetically manipulate Echinococcus will provide an ideal platform for hypothesis-driven research into cestode development in the next years.
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Echinococcus metacestodes as laboratory models for the screening of drugs against cestodes and trematodes. Parasitology 2009; 137:569-87. [PMID: 19765346 DOI: 10.1017/s003118200999117x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Among the cestodes, Echinococcus granulosus, Echinococcus multilocularis and Taenia solium represent the most dangerous parasites. Their larval stages cause the diseases cystic echinococcosis (CE), alveolar echinococcosis (AE) and cysticercosis, respectively, which exhibit considerable medical and veterinary health concerns with a profound economic impact. Others caused by other cestodes, such as species of the genera Mesocestoides and Hymenolepis, are relatively rare in humans. In this review, we will focus on E. granulosus and E. multilocularis metacestode laboratory models and will review the use of these models in the search for novel drugs that could be employed for chemotherapeutic treatment of echinococcosis. Clearly, improved therapeutic drugs are needed for the treatment of AE and CE, and this can only be achieved through the development of medium-to-high throughput screening approaches. The most recent achievements in the in vitro culture and genetic manipulation of E. multilocularis cells and metacestodes, and the accessability of the E. multilocularis genome and EST sequence information, have rendered the E. multilocularis model uniquely suited for studies on drug-efficacy and drug target identification. This could lead to the development of novel compounds for the use in chemotherapy against echinococcosis, and possibly against diseases caused by other cestodes, and potentially also trematodes.
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Abstract
Echinococcus granulosus and Echinococcus multilocularis are cestode parasites, of which the metacestode (larval) stages cause the neglected diseases cystic echinococcosis (CE) and alveolar echinococcosis (AE), respectively. The benzimidazoles albendazole and mebendazole are presently used for the chemotherapeutical treatment, alone or prior to and after surgery. However, in AE these benzimidazoles do not appear to be parasiticidal in vivo. In addition, failures in drug treatments as well as the occurrence of side-effects have been reported, leading to discontinuation of treatment or to progressive disease. Therefore, new drugs are needed to cure AE and CE. Strategies that are currently employed in order to identify novel chemotherapeutical treatment options include in vitro and in vivo testing of broad-spectrum anti-infective drugs or drugs that interfere with unlimited proliferation of cancer cells. The fact that the genome of E. multilocularis has recently been sequenced has opened other avenues, such as the selection of novel drugs that interfere with the parasite signalling machinery, and the application of in silico approaches by employing the Echinococcus genome information to search for suitable targets for compounds of known mode of action.
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Brehm K, Spiliotis M. Recent advances in the in vitro cultivation and genetic manipulation of Echinococcus multilocularis metacestodes and germinal cells. Exp Parasitol 2008; 119:506-515. [DOI: 10.1016/j.exppara.2008.03.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2007] [Revised: 03/13/2008] [Accepted: 03/18/2008] [Indexed: 10/22/2022]
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Spiliotis M, Lechner S, Tappe D, Scheller C, Krohne G, Brehm K. Transient transfection of Echinococcus multilocularis primary cells and complete in vitro regeneration of metacestode vesicles. Int J Parasitol 2007; 38:1025-39. [PMID: 18086473 DOI: 10.1016/j.ijpara.2007.11.002] [Citation(s) in RCA: 105] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2007] [Revised: 11/03/2007] [Accepted: 11/05/2007] [Indexed: 10/22/2022]
Abstract
A major limitation in studying molecular interactions between parasitic helminths and their hosts is the lack of suitable in vitro cultivation systems for helminth cells and larvae. Here we present a method for long-term in vitro cultivation of larval cells of the tapeworm Echinococcus multilocularis, the causative agent of alveolar echinococcosis. Primary cells isolated from cultivated metacestode vesicles in vitro showed a morphology typical of Echinococcus germinal cells, displayed an Echinococcus-specific gene expression profile and a cestode-like DNA content of approximately 300Mbp. When kept under reducing conditions in the presence of Echinococcus vesicle fluid, the primary cells could be maintained in vitro for several months and proliferated. Most interestingly, upon co-cultivation with host hepatocytes in a trans-well system, mitotically active Echinococcus cells formed cell aggregates that subsequently developed central cavities, surrounded by germinal cells. After 4 weeks, the cell aggregates gave rise to young metacestode vesicles lacking an outer laminated layer. This layer was formed after 6 weeks of cultivation indicating the complete in vitro regeneration of metacestode larvae. As an initial step toward the creation of a fully transgenic strain, we carried out transient transfection of Echinococcus primary cells using plasmids and obtained heterologous expression of a reporter gene. Furthermore, we successfully carried out targeted infection of Echinococcus cells with the facultatively intracellular bacterium Listeria monocytogenes, a DNA delivery system for genetic manipulation of mammalian cells. Taken together, the methods presented herein constitute important new tools for molecular investigations on host-parasite interactions in alveolar echinococcosis and on the roles of totipotent germinal cells in parasite regeneration and metastasis formation. Moreover, they enable the development of fully transgenic techniques in this group of helminth parasites for the first time.
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Affiliation(s)
- Markus Spiliotis
- University of Würzburg, Institute of Hygiene and Microbiology, Josef-Schneider-Strasse 2, D97080 Würzburg, Germany
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Hemphill A, Spicher M, Stadelmann B, Mueller J, Naguleswaran A, Gottstein B, Walker M. Innovative chemotherapeutical treatment options for alveolar and cystic echinococcosis. Parasitology 2007; 134:1657-70. [PMID: 17631693 DOI: 10.1017/s0031182007003198] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Echinococcus granulosus and Echinococcus multilocularis are cestode parasites, of which the metacestode (larval) stages cause the diseases cystic echinococcosis (CE) and alveolar echinococcosis (AE), respectively. Albendazole and mebendazole are presently used for chemotherapeutical treatment. However, these benzimidazoles do not appear to be parasiticidal in vivo against AE. In addition, failures in drug treatments as well as the occurrence of side-effects have been reported. New drugs are needed to cure AE and CE, which are considered to be neglected diseases. Strategies currently being implemented to identify novel chemotherapeutical treatment options include (i) conventional primary in vitro testing of broad-spectrum anti-infective drugs, either in parallel with, or followed by, animal experimentation; (ii) studies of drugs which interfere with the proliferation of cancer cells and of Echinococcus metacestodes; (iii) exploitation of the similarities between the parasite and mammalian signalling machineries, with a special focus on targeting specific signalling receptors; (iv) in silico approaches, employing the current Echinococcus genomic database information to search for suitable targets for compounds with known modes of action. In the present article, we review the efforts toward obtaining better anti-parasitic compounds which have been undertaken to improve chemotherapeutical treatment of echinococcosis, and summarize the achievements in the field of host-parasite interactions which may also lead to new immuno-therapeutical options.
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Affiliation(s)
- A Hemphill
- Institute of Parasitology, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
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Ali-Khan Z, Li W, Chan SL. Animal model for the pathogenesis of reactive amyloidosis. ACTA ACUST UNITED AC 2005; 12:297-302. [PMID: 15275180 DOI: 10.1016/0169-4758(96)10032-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The pathogenesis of amyloidosis is not well understood. Here, Zafer Ali-Khan, Weihua Li and Sic L. Chan present a metazoan parasite mouse model of reactive amyloidosis, review the relationship between chronic inflammation and multiorgan AA amyloidosis and postulate how ubiquitin might function in the processing of serum amyloid A and in AA amyloid formation in the endosomes-lysosomes of activated murine reticuloendothetial cells.
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Affiliation(s)
- Z Ali-Khan
- Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, Quebec, Canada.
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17
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Sbihi Y, Gil JR, Alvarez PA, Orduña A, Rodríguez‐Torres A, Osuna A. Development of a dipstick dye immunoassay for diagnosing hydatidosis. J Clin Lab Anal 2003; 17:219-22. [PMID: 14614744 PMCID: PMC6808177 DOI: 10.1002/jcla.10097] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2003] [Accepted: 04/17/2003] [Indexed: 11/10/2022] Open
Abstract
We have developed a kit to diagnose hydatidosis, based on the detection of specific antibodies. This disease, caused by larvae of the cestode Echinococcus granulosus, is a zoonosis commonly found throughout the world. The diagnostic kit discriminates between positive and negative cases in a way that is easily interpreted, i.e., positive cases form a colored band on an inert substrate. The results show test sensitivity to be some 94.87% and specificity 85.71%, which is comparable to those of the ELISA technique. The high sensitivity and specificity of this test affords the great advantage of speed in diagnosing this parasitosis. No other equipment or procedure is required.
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Affiliation(s)
- Younes Sbihi
- Instituto de Biotecnología, Campus Fuentenueva, Facultad de Ciencias, Universidad de Granada, Granada, Spain
| | - José R. Gil
- Instituto de Biotecnología, Campus Fuentenueva, Facultad de Ciencias, Universidad de Granada, Granada, Spain
| | - Pedro A. Alvarez
- Instituto de Biotecnología, Campus Fuentenueva, Facultad de Ciencias, Universidad de Granada, Granada, Spain
| | - Antonio Orduña
- Departamento de Microbiología, Facultad de Medicina, Valladolid, Spain
| | | | - Antonio Osuna
- Instituto de Biotecnología, Campus Fuentenueva, Facultad de Ciencias, Universidad de Granada, Granada, Spain
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18
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MacIntyre AR, Dixon JB, Bleakley JS, Green JR. Echinococcus granulosus: assays for hydatid immunoregulatory factors using established lymphoid cell lines. Parasite Immunol 2000; 22:475-85. [PMID: 11012973 DOI: 10.1046/j.1365-3024.2000.00327.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Mitosis, mitochondrial metabolic rate and proliferation were measured in established lymphoid cell lines exposed to chromatographic fractions of equine Echinococcus granulosus hydatid fluid. In several cell lines, one or more of the three parameters were modified by the exposure. As an assay for potential immunoregulatory activity, the method was simple and repeatable. The following novel observations were made: (1) Mitotic reaction was found among lines of T-cell, B-cell and macrophage origin; (2) mitosis was accompanied by proliferation in the B-cell lines, B9 and A20, and in the macrophage lines, HL-60 and P388d. With mitotically responsive T-cells, proliferation was slight in CTLL-2 and absent in D10, implying cell-cycle modification; (3) mitotic responsiveness tended to occur in cell lines with mature characteristics; (4) among cytokine-dependent cell lines, hydatid fluid FPLC fraction 1 mimicked IL-1 and several fractions mimicked IL-2 and IL-6 in the maintenance of mitosis; and (5) there was significant statistical interaction between the influences of mammalian cytokines and hydatid fluid fractions, implying that the propensity of antigenically unprimed lymphoid cells to be regulated by E. granulosus is conditioned by cytokine activity.
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Affiliation(s)
- A R MacIntyre
- Department of Veterinary Pathology, Department of Mathematical Studies, University of Liverpool, Liverpool L69 3BX, UK
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19
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Reuter S, Schirrmeister H, Kratzer W, Dreweck C, Reske SN, Kern P. Pericystic metabolic activity in alveolar echinococcosis: assessment and follow-up by positron emission tomography. Clin Infect Dis 1999; 29:1157-63. [PMID: 10524957 DOI: 10.1086/313438] [Citation(s) in RCA: 75] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Information on parasite viability in alveolar echinococcosis (AE) cannot be obtained by conventional imaging techniques. We evaluated the glucose metabolism of AE lesions by use of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) in 12 inoperable patients. Eight patients showed either perilesional or focal enhancement ("hot spots"), whereas 4 patients had nonenhancing (metabolically inactive) lesions. With PET, necrotic parasitic lesions and areas of enhanced metabolic activity could be clearly discriminated. Most notably, 3 of 8 patients with metabolically active lesions who were reexamined after chemotherapy treatment clearly showed improvement: the initial surrounding hot spots had disappeared in 2 of them, and had significantly decreased in 1. PET may prove valuable in assessing the efficacy of chemotherapy by showing the disappearance of metabolic activity and may also be useful for timely detection of relapses and metastases. Although costly and not readily available, FDG-PET is a promising tool toward improved management of AE and may thus help lower costs of long-term chemotherapy.
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Affiliation(s)
- S Reuter
- Section of Infectious Diseases and Clinical Immunology, Department of Medicine III, University Hospital of Ulm, 89070 Ulm, Germany
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20
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Yamashita K, Uchino J, Sato N, Furuya K, Namieno T. Establishment of a primary culture of Echinococcus multilocularis germinal cells. J Gastroenterol 1997; 32:344-50. [PMID: 9213248 DOI: 10.1007/bf02934491] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
This study was designed to establish an in vitro primary culture of germinal cells of Echinococcus multilocularis, a parasite that causes alveolar echinococcosis of the liver (AEL). We also investigated the temperature-dependency of the cultured cells. The germinal cells, which originated from a human lesion, were cultured by an original fluid-suspension method at 25 degrees C or 37 degrees C for 4 weeks. Anchorage-dependent and -independent cells were observed by light microscopy, transmission electron microscopy, and immunocytochemistry to confirm their origin. Cell number and viability were examined by immunocytochemistry and mitochondrial exclusion test. The cultured cells were also inoculated into jirds (Meriones unguiculatus) to evaluate metacestode formation. Morphology and immunocytochemistry showed that the cultured cells were typically germinal cells. The cell number declined gradually over the 4-week culture period, but viability remained at 50% at 3 weeks. These findings were not associated with either of the two culture temperatures; moreover, host-associated cells were not noted in the cultured cells at 25 degrees C. The implanted cells formed metacestodes in the jird peritoneal cavity, and their histology demonstrated mature and typical alveolar-type echinococcal cysts. We successfully established an in vitro primary culture of germinal cells. This should contribute to future studies, and, hence, a better outcome for patients with AEL.
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Affiliation(s)
- K Yamashita
- First Department of Surgery Hokkaido University School of Medicine, Sapporo, Japan
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21
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Abstract
Hydatids, the intermediate stages, or metacestodes, of the tapeworm genus, Echinococcus, present a major immunological problem; they survive, grow and metastasize in immunized hosts which are protected against reinfection and possess effector mechanisms capable of killing the parasite. Explanations for this state of concomitant immunity have been made from investigations of avoidance strategies, genetics and quantitative hydatid growth. The latter study suggests that the host-parasite relationship is sustained as a dynamic equilibrium between parasite growth and acquired immunity, the balance being subject to mutual regulation and including the possibility of spontaneous rejection of the parasite. Two immunoregulatory, or cytokine-like, factors have been detected in hydatids of Echinococcus spp. One appears to be a mediator of the previously reported mitogenic effects of hydatids. Recent evidence has linked these effects to generation of T-suppressor populations. The second factor interferes with the interaction of macrophages and T-cells, mimics the effect of metacestode infection in impairing the accessory action of macrophages in lymphoproliferative responses, and is suppressive for rosette-forming cell responses against third-party antigens. It is suggested that these factors form part of a primary homeostatic mechanism regulating hydatid growth and immunity.
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Affiliation(s)
- J B Dixon
- Department of Veterinary Pathology, University of Liverpool, U.K
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22
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Gabrion C, Walbaum S, al Nahhas S, Mesnil M, Petavy AF. Echinococcus multilocularis protoscoleces and hepatic cell activity in vitro. Int J Parasitol 1995; 25:127-30. [PMID: 7797364 DOI: 10.1016/0020-7519(94)00086-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
E. multilocularis protoscoleces were co-cultured with hepatic cells in the presence of IAR 20 or BALB/c 3T3 cells. Hepatocyte activity was determined by assaying transferrin and albumin secretion in culture media. The level of these 2 plasma proteins is higher in hepatic/BALB/c 3T3 co-culture medium. In the presence of parasites, the transferrin level is unchanged while the production of albumin is stimulated during the first 48 h. Our results suggest that the albumin production could be attributed to a complex cellular cooperation between hepatocytes and activated Kupffer cells as previously observed in the acute inflammatory reaction.
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Affiliation(s)
- C Gabrion
- Laboratoire de Parasitologie comparée, URA 698 CNRS, Université Montpellier II, France
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Abstract
A cell line of larval Echinococcus multilocularis has been established from an echinococcal cyst excised surgically from a patient with alveolar hydatid disease. A standardized procedure established for the preparation and continuation of primary cultures was applied to isolate the E. multilocularis cells from the tissue fragments. Trypsin was used for the enzymatic release of the monodispersed cells from the tissue fragments and for dispersing monolayers. The culture medium was RPMI 1640 with 10% fetal calf serum. Cell supports were collagen-coated plastic dishes and flasks. The morphological features of the cultured cells showed spindle-like cells during the first few subcultures, and then polygonal or star-like cells. Population doubling time at passage 34 was approximately 23 h and plating efficiency at the same passage was 15%. Chromosome numbers obtained from 70 metaphase plates at passage 40 ranged between 14 and 104 and cells with 91-100 chromosomes were clearly predominant. The chromosomes could be morphologically classified into telocentric, subtelocentric, and metacentric types. Over 90% of the chromosomes were of the telocentric type. Cells collected at passage 57 were intraperitoneally inoculated into two cotton rats (Sigmodon hispidus) at a cell concentration of 10(7) and the rats were sacrificed 100 days later. It was found that the two rats had echinococcal cyst masses in the peritoneal cavity. This result indicates that our isolated cells are germinal cells with ability to differentiate into cystic structures in vivo.
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Affiliation(s)
- K Furuya
- Hokkaido Institute of Public Health, Sapporo, Japan
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Bresson-Hadni S, Liance M, Meyer JP, Houin R, Bresson JL, Vuitton DA. Cellular immunity in experimental Echinococcus multilocularis infection. II. Sequential and comparative phenotypic study of the periparasitic mononuclear cells in resistant and sensitive mice. Clin Exp Immunol 1990; 82:378-83. [PMID: 2242619 PMCID: PMC1535102 DOI: 10.1111/j.1365-2249.1990.tb05457.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Cellular immune responses have been shown to be associated with differential evolutions of E. multilocularis infection in intermediate hosts. A relationship between course of delayed-type hypersensitivity (DTH) against parasitic antigens and receptivity of murine strains has been demonstrated recently. The aim of this study was to correlate resistance and sensitivity to E. multilocularis infection with the phenotypic patterns of cells within the periparasitic granuloma. Evolution of the ratios, macrophages/T lymphocyte and Ly1/Ly2 T lymphocytes, was associated with the receptivity of the strains. Persistence of numerous L3T4 + T lymphocytes and low numbers of macrophages and Ly2 + T lymphocytes were observed in the 'resistant' C57BL.10 mice. Comparison of the results with course of the DTH against E. multilocularis antigens showed that the particular phenotypic pattern observed in resistant mice was associated with a particular profile of DTH after infection. These results and similar observations in human alveolar echinococcosis suggest that cell composition of the periparasitic granuloma might be of crucial importance in controlling the spontaneous development of E. multilocularis larvae in the intermediate host.
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Affiliation(s)
- S Bresson-Hadni
- Groupe de Recherche sur l'Echinococcose Alvéolaire (AREA), Faculté de Médecine, Besançon, France
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25
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Ali-Khan Z, Sipe JD, Du T, Riml H. Echinococcus multilocularis: relationship between persistent inflammation, serum amyloid A protein response and amyloidosis in four mouse strains. Exp Parasitol 1988; 67:334-45. [PMID: 3191961 DOI: 10.1016/0014-4894(88)90080-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
LPS-hyporesponsive (C3H/HeJ) and LPS-sensitive (C57BL/6, CBA/J, C3H/HeSn) strains of mice were infected intraperitoneally with 50 alveolar hydatid cysts (AHC) to assess the effect of protracted severe inflammation on serum amyloid A protein (SAA) concentrations, splenic amyloid deposition, and pre- and postamyloidotic alterations in the splenic architecture. In general, the SAA concentrations in all the four mouse strains showed a moderate but steady increase throughout the course of infection. Splenic amyloid deposition commenced between 6 to 8 weeks postinfection (p.i.) when the SAA concentrations were relatively low and increased progressively until 12 weeks p.i. when 52 to 78% of the splenic parenchyma was obliterated. CBA mice which harbored the largest AHC throughout the 12-week course of infection showed the poorest SAA and amyloid responses; the situation was reversed in the C3H/HeSn strain. Histologically, most of the splenic follicles, during the stage of maximum amyloid deposition, appeared hypocellular. Their T-cell-dependent periarterial sinuses were either totally depleted of cells or contained plasma cells or myeloid cells. These results show that (a) there is no direct correlation between the intensity of inflammation, SAA concentrations, or amounts of amyloid deposition in either of the four mouse strains and (b) amyloidosis secondary to AHC infection differs from other experimental mouse models of amyloidosis in the magnitude of SAA elevation during the preamyloid phase.
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Affiliation(s)
- Z Ali-Khan
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
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Alkarmi TO, Alshakarchi Z, Behbehani K. Echinococcus multilocularis: the non-specific binding of different species of immunoglobulins to alveolar hydatid cysts grown in vivo and in vitro. Parasite Immunol 1988; 10:443-57. [PMID: 2459652 DOI: 10.1111/j.1365-3024.1988.tb00234.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Alveolar hydatid cysts (AHC) were isolated from C57BL/6J and BALB/c mice at 8 and 12 weeks post-infection from subcutaneous and intraperitoneal foci and cultured in vitro. Freshly isolated as well as in vitro-grown cysts were incubated with Fc or F(ab')2 fragments of human, rabbit, mouse, goat or sheep immunoglobulins, then washed and incubated with a fluorescein-conjugated rabbit or goat F(ab')2 fraction of antisera to each of the above primary sera. Significant fluorescence on the surface of AHC was detected when they were incubated with human, rabbit or mouse Fc fractions followed by the addition of goat or rabbit fluorescein-conjugated antiserum. No fluorescence was detected when the AHC were incubated with the F(ab')2 fragments and fluorescein-conjugated antiserum, except when the primary antiserum was mouse F(ab')2 fractions. Cysts grown in vitro retained their binding ability to human, rabbit or mouse Fc fractions. However, the intensity of fluorescence decreased proportionally with time. The maximum intensity of staining was observed with small cysts. Large cysts showed diminished fluorescence. The non-specific binding of human, mouse or rabbit immunoglobulins (Fc fractions) to AHC was also confirmed by rosetting with sheep erythrocytes (SRBC) which suggests that the larvae of Echinococcus multilocularis may utilize the presence of Fc receptors on their surface in order to elude immune destruction by the host.
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Affiliation(s)
- T O Alkarmi
- Department of Microbiology, Faculty of Medicine, Kuwait University
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27
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Dieckmann A, Frank W. Isolation of viable germinal cells from Echinococcus multilocularis. Parasitol Res 1988; 74:297-8. [PMID: 2834715 DOI: 10.1007/bf00539582] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- A Dieckmann
- Fachgebiet Parasitologie (Institut für Zoologie), Universität Hohenheim, Stuttgart, Federal Republic of Germany
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28
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Abstract
Mongolian gerbils (Meriones unguiculatus) inoculated intraperitoneally with three acephalic cysts of Echinococcus multilocularis were very susceptible to infection. Aspects of the responses of gerbils to this infection were examined to determine if they could be related to the progress of the infection. Hematologic changes observed during the infection included anemia, reticulocytosis, lymphocytopenia, neutrophilia, monocytosis, and eosinopenia; these changes were related to the size of the infection. Infected gerbils also produced specific protein-A binding antibodies to E. multilocularis. At 14 weeks after inoculation, infected gerbils showed splenomegaly and somewhat elevated serum transaminase levels, although serum 5'-nucleotidase levels were normal.
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