[show abstract][hide abstract] ABSTRACT: Echinococcosis is a major parasitic zoonosis of public health importance in western China. In 2004, the Chinese Ministry of Health estimated that 380,000 people had the disease in the region. The Qinghai-Tibet Plateau is highly co-endemic with both alveolar echinococcosis (AE) and cystic echinococcosis (CE). In the past years, the Chinese government has been increasing the financial support to control the diseases in this region. Therefore, it is very important to identify the significant risk factors of the diseases by reviewing studies done in the region in the past decade to help policymakers design appropriate control strategies.Review: Selection criteria for which literature to review were firstly defined. Medline, CNKI (China National Knowledge Infrastructure), and Google Scholar were systematically searched for literature published between January 2000 and July 2011. Significant risk factors found by single factor and/or multiple factors analysis were listed, counted, and summarized. Literature was examined to check the comparability of the data; age and sex specific prevalence with same data structures were merged and used for further analysis.A variety of assumed social, economical, behavioral, and ecological risk factors were studied on the Plateau. Those most at risk were Tibetan herdsmen, the old and female in particular. By analyzing merged comparable data, it was found that females had a significant higher prevalence, and a positive linearity relationship existed between echinococcosis prevalence and increasing age. In terms of behavioral risk factors, playing with dogs was mostly correlated with CE and/or AE prevalence. In terms of hygiene, employing ground water as the drinking water source was significantly correlated with CE and AE prevalence. For definitive hosts, dog related factors were most frequently identified with prevalence of CE or/and AE; fox was a potential risk factor for AE prevalence only. Overgrazing and deforestation were significant for AE prevalence only.
Tibetan herdsmen communities were at the highest risk of echinococcosis prevalence and should be the focus of echinococcosis control. Deworming both owned and stray dogs should be a major measure for controlling echinococcosis; treatment of wild definitive hosts should also be considered for AE endemic areas. Health education activities should be in concert with the local people's education backgrounds and languages in order to be able to improve behaviors. Further researches are needed to clarify the importance of wild hosts for AE/CE prevalence, the extent and range of the impacts of ecologic changes (overgrazing and deforestation) on the AE prevalence, and risk factors in Tibet.
[show abstract][hide abstract] ABSTRACT: Flavonoids have antitumoral properties and may be attractive candidates as anticancer therapy. Isoliquiritigenin which is a constituent of licorice (Glycyrrhiza inflata), a plant commonly used in traditional Uyghur medicine in Xinjiang, China, was studied for antiproliferative and apoptotic activity in human cervical cancer cells, Ca Ski, SiHa, HeLa, and C-33A. Its molecular mechanism of action was specifically examined in Ca Ski cells. Isoliquiritigenin decreased cell viability, induced cell accumulation in G2/M and morphological and biochemical features of apoptosis in the four cancer cell lines. In Ca Ski cells, isoliquiritigenin led to a downregulation of HPV16 E6 expression associated with an increase of p53 and p21 levels, enhanced expression of Bax and decreased expression of Bcl-2 and Bid proform triggering dissipation of the mitochondrial membrane potential, released cytochrome c to the cytosol followed by activation of caspase cascade with cleavage of caspase-9, caspase-3, and PARP. Caspase-8 was also cleaved. Moreover treatment with a pan-caspase inhibitor prevented apoptosis. As Ca Ski cells are representative of carcinoma naturally occurring in the cervix, our results suggest a potential benefit of isoliquiritigenin for cervical cancer prevention and treatment.
[show abstract][hide abstract] ABSTRACT: SUMMARY Recent changes in the epidemiology of alveolar echinococcosis (AE) in Eurasia have led to increasing concerns about the risk of human AE and the need for a thorough evaluation of the epidemiological situation. The aim of this study was to explore the use of a National Register to detect complex distribution patterns on several scales. The data were human AE cases from the FrancEchino register, diagnosed in France from 1982 to 2011. We used the Kulldorff spatial scan analysis to detect non-random locations of cases. We proposed an exploratory method that was based on the successive detection of nested clusters inside each of the statistically significant larger clusters. This method revealed at least 4 levels of disease clusters during the study period. The spatial variations of cluster location over time were also shown. We conclude that National Human AE registers, although not exempted from epidemiological biases, are currently the best way to achieve an accurate representation of human AE distribution on various scales. Finally, we confirm the multi-scale clustered distribution of human AE, and we hypothesize that our study may be a reasonable starting point from which to conduct additional research and explore the processes that underlie such distributions.
[show abstract][hide abstract] ABSTRACT: (18)F-FDG PET has already proved its usefulness in the follow-up of patients with alveolar echinococcosis (AE) and has been proposed as a surrogate marker for therapeutic decisions on structured treatment interruption by benzimidazoles. However, standard PET acquisition (1 h after (18)F-FDG injection) lacks sensitivity, and the parasite may stay viable even if (18)F-FDG perilesional uptake has disappeared. The aim of our study was to evaluate the usefulness of delayed (18)F-FDG PET in the management of AE patients. METHODS: During a 6-y period, 120 PET scans using (18)F-FDG were obtained for 70 AE patients treated by benzimidazoles, without selection. All patients underwent whole-body imaging on a PET/CT device 1 h after (18)F-FDG injection (4 MBq/kg), as well as an acquisition focused on the liver 3 h after the injection. We also analyzed the results of serologic tests. RESULTS: Of the 57 scans considered negative at the standard acquisition, 13 (22.8%) became clearly positive at the delayed acquisition, and 6 (10.5%) became indeterminate at the delayed acquisition. Furthermore, 20 of 22 scans interpreted as indeterminate at the standard acquisition were considered positive because of clear perilesional (18)F-FDG uptake at the delayed acquisition. Thus, delayed acquisition changed the interpretation in 32.5% of cases. Moreover, of 44 patients treated by benzimidazoles and followed for more than 2 y by regular (18)F-FDG PET scans and specific AE serology, 11 (25%) presented pathologic (18)F-FDG uptake at the delayed acquisition but not at the standard one. In these patients, the treatment was continued despite negative results on standard (18)F-FDG PET and negative serologic findings. On the other hand, in 7 patients with negative delayed (18)F-FDG PET and negative serology, the treatment was safely interrupted with no evidence of disease recurrence during 8-37 mo (mean, 23 mo). CONCLUSION: Our study clearly demonstrated that delayed (18)F-FDG PET greatly facilitated the differentiation between active and inactive liver lesions in AE patients. Also, our results strongly suggested that the combination of delayed (18)F-FDG PET and specific serology would prevent most of the recurrences observed after premature interruption of the treatment based only on standard (18)F-FDG PET.
Journal of Nuclear Medicine 01/2013; · 5.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: We report the 30-yr history of a well-documented human case of alveolar echinococcosis, with a lung lesion at presentation followed by the discovery of a liver lesion, both removed by surgery. Subsequently, within the 13 years following diagnosis, metastases were disclosed in eye, brain and skull, as well as additional lung lesions. This patient had no immune suppression, and did not have the genetic background known to predispose to severe alveolar echinococcosis; it may thus be hypothesized that iterative multi-organ involvement was mostly due to the poor adherence to benzimidazole treatment for the first decade after diagnosis. Conversely, after a new alveolar echinococcosis recurrence was found in the right lung in 1994, the patient accepted to take albendazole continuously at the right dosage. After serology became negative and a fluoro-deoxy-glucose-Positron Emission Tomography performed in 2005 showed a total regression of the lesions in all organs, albendazole treatment could be definitively withdrawn. In 2011, the fluoro-deoxy-glucose-Positron Emission Tomography showed a total absence of parasitic metabolic activity and the patient had no clinical symptoms related to alveolar echinococcosis.The history of this patient suggests that multi-organ involvement and alveolar echinococcosis recurrence over time may occur in non-immune suppressed patients despite an apparently "radical" surgery. Metastatic dissemination might be favored by a poor adherence to chemotherapy. Combined surgery and continuous administration of albendazole at high dosage may allow alveolar echinococcosis patients to survive more than 30 years after diagnosis despite multi-organ involvement.
Annals of Clinical Microbiology and Antimicrobials 01/2013; 12(1):1. · 1.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: Human alveolar echinococcosis (AE) is a parasitic zoonosis with intermediate (rodents and lagomorphs) and final hosts (carnivores, mainly fox but also dogs). The latter can transmit the parasite to humans, by their feces, which are contaminated by the oncospheres of Echinococcus multilocularis, the larvae of which develop in the liver like a slow cancer. This chronically progressive disease may involve adjacent tissues and organs. Distant metastases may also be observed. Infected patient are frequently detected at earlier asymptomatic stage. Increasing fox populations, their invasion of the cities and the detection of the parasite in foxes from previously parasite-free areas seem to currently modify the epidemiology of AE. Patients’ management must be multidisciplinary and includes (i) radical liver resection whenever possible, (ii) avoidance of palliative surgical procedures, (iii) use of interventional radiology or endoscopy to treat biliary and vascular complications whenever possible, (iv) indication of liver transplantation only in patients with life-threatening complications, (v) treatment of all patients without exception by albendazole for at least two years after radical surgery and long-term (at least several years) in non operated cases, (vi) use of positron-emission tomography combined with computed tomography (PET-CT) and specific serological tools to assess the functional activity of the lesions and monitor treatment, (vii) regular monitoring of albendazole plasmatic levels. Patients’ survival and quality of life have improved very substantially, due to optimized care strategy.
[show abstract][hide abstract] ABSTRACT: Alveolar echinococcosis (AE) is characterized by the development of irreversible fibrosis and of immune tolerance towards Echinococcus multilocularis (E. multilocularis). Very little is known on the presence of transforming growth factor-β (TGF-β) and other components of TGF-β/Smad pathway in the liver, and on their possible influence on fibrosis, over the various stages of infection. Using Western Blot, qRT-PCR and immunohistochemistry, we measured the levels of TGF-β1, TGF-β receptors, and down-stream Smads activation, as well as fibrosis marker expression in both a murine AE model from day 2 to 360 post-infection (p.i.) and in AE patients. TGF-β1, its receptors, and down-stream Smads were markedly expressed in the periparasitic infiltrate and also in the hepatocytes, close to and distant from AE lesions. Fibrosis was significant at 180 days p.i. in the periparasitic infiltrate and was also present in the liver parenchyma, even distant from the lesions. Over the time course after infection TGF-β1 expression was correlated with CD4/CD8 T-cell ratio long described as a hallmark of AE severity. The time course of the various actors of the TGF-β/Smad system in the in vivo mouse model as well as down-regulation of Smad7 in liver areas close to the lesions in human cases highly suggest that TGF-β plays an important role in AE both in immune tolerance against the parasite and in liver fibrosis.
PLoS ONE 01/2013; 8(2):e55379. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) can be used to evaluate parasitic activity in alveolar echinococcosis (AE) as visualization of host–parasite immune reaction around the lesions. We performed a retrospective interpretation of PET and MR (magnetic resonance) images in 24 patients with AE to compare the results of metabolic imaging to Kodama et al. anatomical classification. All patients underwent hepatic MRI and dual-time point FDG-PET (1 hour and 3 hours after injection), improving sensitivity of standard FDG-PET in AE. The comparison of the images showed perilesional 18F-FDG uptake in all seven patients with type 1 (multiple microcysts without a solid component) and type 2 (multiple microcysts with a solid component) lesions and in ten of 12 patients with type 3 lesions (a solid component surrounding cysts and microcysts). No abnormal perilesional uptake was observed at standard and delayed PET acquisitions in two of 12 patients with type 3 lesions and in all five patients with type 4 (a solid component without microcysts) and type 5 (a large liquid cavity without microcysts) lesions. Our study demonstrates a strong correlation between anatomical “microcystic” aspect and metabolic activity of AE lesions in 89.5% of cases. Thus, microcysts and metabolic perilesional activity seem correlated to parasite activity, which suggests an important role to combined follow-up of AE patients, through multimodality imaging using MRI and 18F-FDG-PET scan.
[show abstract][hide abstract] ABSTRACT: Alveolar echinococcosis (AE) is characterized by the tumor-like growth of Echinococcus (E.) multilocularis. Very little is known on the influence of helminth parasites which develop in the liver on the proliferation/growth arrest metabolic pathways in the hepatocytes of the infected liver over the various stages of infection.
Using Western blot analysis, qPCR and immunohistochemistry, we measured the levels of MAPKs activation, Cyclins, PCNA, Gadd45β, Gadd45γ, p53 and p21 expression in the murine AE model, from day 2 to 360 post-infection. Within the early (day 2-60) and middle (day60-180) stages, CyclinB1 and CyclinD1 gene expression increased up to day30 and then returned to control level after day60; Gadd45β, CyclinA and PCNA increased all over the period; ERK1/2 was permanently activated. Meanwhile, p53, p21 and Gadd45γ gene expression, and caspase 3 activation, gradually increased in a time-dependent manner. In the late stage (day180-360), p53, p21 and Gadd45γ gene expression were significantly higher in infected mice; JNK and caspase 3 were activated. TUNEL analysis showed apoptosis of hepatocytes. No significant change in CyclinE, p53 mRNA and p-p38 expression were observed at any time.
Our data support the concept of a sequential activation of metabolic pathways which 1) would first favor parasitic, liver and immune cell proliferation and survival, and thus promote metacestode fertility and tolerance by the host, and 2) would then favor liver damage/apoptosis, impairment in protein synthesis and xenobiotic metabolism, as well as promote immune deficiency, and thus contribute to the dissemination of the protoscoleces after metacestode fertility has been acquired. These findings give a rational explanation to the clinical observations of hepatomegaly and of unexpected survival of AE patients after major hepatic resections, and of chronic liver injury, necrosis and of hepatic failure at an advanced stage and in experimental animals.
PLoS ONE 01/2012; 7(1):e30127. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: In the first part of this review, some behavioural and environmental risk factors playing important roles in the development of Kazakh's oesophageal squamous cell carcinoma (OSCC) were presented. Although all individuals have been exposed to the same environment and share the same behaviour, some of them will not develop OSCC. Thus, gene susceptibility and/or gene polymorphism are unavoidably involved. The molecular events underlying the initiation and progression of OSCC remain, however, poorly understood. In the second part of our review of OSCC in northwestern China, especially in the high-risk Kazakh population, some recent progress in the study of the molecular biology underlying oesophageal carcinogenesis, including chromosome deletions and loss of heterozygocity, polymorphisms of genes involved in xenobiotic metabolizing and DNA repair, and genetic alterations of transcriptional factors and apoptosis genes are presented. Results obtained in this high-risk population are compared with those obtained in other areas that are also known to be at high risk for OSCC, and whenever possible, with those studies performed in European, American or Australian low-risk areas. Recent advances in the investigation of the proteomics and microRNA biomarkers potentially useful for an earlier diagnosis and/or prognosis of OSCC are also discussed.
European journal of gastroenterology & hepatology 11/2011; 23(12):1087-99. · 1.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Since the first 2 cases observed in southern Germany and the correct identification of a parasite at the origin of the disease by the famous scientist Rudolf Virchow in 1855, the borders of the endemic area of alveolar echinococcosis (AE) have never stopped to expand. The parasite was successively recognized in Switzerland, then in Russia, Austria and France which were long considered as the only endemic areas for the disease. Cases were disclosed in Turkey in 1939; then much attention was paid to Alaska and to Hokkaido, in Japan. The situation totally changed in 1991 after the recognition of the Chinese endemic areas by the international community of scientists. The world map was completed in the beginning of the 21st century by the identification of AE in most of the countries of central/eastern Europe and Baltic States, and by the recognition of cases in central Asia. Up to now, the disease has however never been reported in the South hemisphere and in the United Kingdom. In the mid-1950s, demonstration by Rausch and Schiller in Alaska, and by Vogel in Germany, of the distinction between 2 parasite species responsible respectively for cystic echinococcosis (“hydatid disease”) and AE put an end to the long-lasting debate between the "dualists", who believed in that theory which eventually proved to be true, and the "unicists", who believed in a single species responsible for both diseases. At the end of the 20th century, molecular biology fully confirmed the "dualist" theory while adding several new species to the initially described E. granulosus; within the past decade, it also confirmed that little variation existed within Echinococcus (E.) multilocularis species, and that AE-looking infection in some intermediate animal hosts on the Tibetan plateau was indeed due to a new species, distinct from E. multilocularis, named E. shiquicus. Since the 1970s, the unique ecological interactions between the landscape, the hosts, and E. multilocularis have progressively been delineated. The important role of the rodent/lagomorph reservoir size for the maintenance of the parasite cycle has been recognized within the last 2 decades of the 20th century. And the discovery of a close relationship between high densities of small mammals and particularities in land use by agriculture/forestry has stressed the responsibility of political/economic decisions on the contamination pressure. Urbanization of foxes in Europe and Japan and the major role of dogs in China represent the new deals at the beginning of the 21st century regarding definitive hosts and prevention measures.
Chinese medical journal 09/2011; 124(18):2943-53. · 0.90 Impact Factor
[show abstract][hide abstract] ABSTRACT: Liver transplantation (LT) is currently contraindicated in patients with residual or metastatic alveolar echinococcosis (AE) lesions. We evaluated the long-term course of such patients who underwent LT and were subsequently treated with benzimidazoles. Clinical, imaging, serological, and therapeutic data were collected from 5 patients with residual/recurrent AE lesions who survived for more than 15 years. Since 2004, [(18) F]-2-fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) images were available, and the levels of serum antibodies (Abs) against Echinococcus multilocularis-recombinant antigens were evaluated. Median survival time after LT was 21 years. These patients were from a prospective cohort of 23 patients with AE who underwent LT: 5 of 8 patients with residual/recurrent AE and 4 of 9 patients without residual/recurrent AE were alive in September 2009. High doses of immunosuppressive drugs, the late introduction of therapy with benzimidazoles, its withdrawal due to side effects, and nonadherence to this therapy adversely affected the prognosis. Anti-Em2(plus) and anti-rEm18 Ab levels and standard FDG-PET enabled the efficacy of therapy on the growth of EA lesions to be assessed. However, meaningful variations in Ab levels were observed below diagnostic cutoff values; and in monitoring AE lesions, images of FDG uptake taken 3 hours after its injection were more sensitive than images obtained 1 hour after its injection. In conclusion, benzimidazoles can control residual/recurrent AE lesions after LT. Using anti-rEm18 or anti-Em2(plus) Ab levels and the delayed acquisition of FDG-PET images can improve the functional assessment of disease activity. The potential recurrence of disease, especially in patients with residual or metastatic AE lesions, should not be regarded as a contraindication to LT when AE is considered to be lethal in the short term.
[show abstract][hide abstract] ABSTRACT: Alveolar echinococcosis (AE) is a rare disease in humans, caused by the larval stage of the fox tapeworm Echinococcus multilocularis.
We present here 387 detailed AE cases diagnosed in France from 1982 to 2007 actively identified by a retrospective survey performed in 1997-1998 and prospectively thereafter.
Male:female ratio was 1.03 and mean age 57.8 years at time of diagnosis. Among the 362 complete files (including 347 non dead-out and 15 dead-out lesions), 73% of the patients were symptomatic at first admittance. Among them, 83% presented with clinical patterns evocative either of a digestive or a hepatic disorder. Other symptomatic patients presented with erratic clinical pictures, generally due to metastasis or extra-hepatic location of the parasite. Except for a few patients with particularly severe AE who died shortly after the diagnosis, most patients were treated using benzimidazoles. Their mortality tends to merge with that of the general French population, matched by sex, age, and calendar year. This study also highlights an unexpectedly high frequency of blood-tied family cases (13% of patients submitted to a specific questionnaire).
Even though the broad set of clinical features provoked by E. multilocularis makes AE a potential diagnostic trap for many physicians, our study revealed an improvement of its prognosis. However, as shown by our findings about the frequency of family cases, there is still a need for studies aimed at better describing this uncommon parasitic disease.
Journal of Hepatology 02/2011; 55(5):1025-33. · 9.86 Impact Factor
[show abstract][hide abstract] ABSTRACT: Alveolar echinococcosis (AE) is a severe chronic parasitic disease which behaves like a slow-growing liver cancer. Clinical observations suggest that the parasite, Echinococcus multilocularis (E. multilocularis) influences liver homeostasis and hepatic cell metabolism. However, this has never been analyzed during the time course of infection in the common model of secondary echinococcosis in experimental mice.
Gene expression profiles were assessed using DNA microarray analysis, 1, 2, 3 and 6 months after injection of E. multilocularis metacestode in the liver of susceptible mice. Data were collected at different time points to monitor the dynamic behavior of gene expression. 557 differentially expressed genes were identified at one or more time points, including 351 up-regulated and 228 down-regulated genes. Time-course analysis indicated, at the initial stage of E. multilocularis infection (month 1-2), that most of up-regulated pathways were related to immune processes and cell trafficking such as chemokine-, mitogen-activated protein kinase (MAPK) signaling, and down-regulated pathways were related to xenobiotic metabolism; at the middle stage (month 3), MAPK signaling pathway was maintained and peroxisome proliferator-activated receptor (PPAR) signaling pathway emerged; at the late stage (month 6), most of up-regulated pathways were related to PPAR signaling pathway, complement and coagulation cascades, while down-regulated pathways were related to metabolism of xenobiotics by cytochrome P450. Quantitative RT-PCR analysis of a random selection of 19 genes confirmed the reliability of the microarray data. Immunohistochemistry analysis showed that proliferating cell nuclear antigen (PCNA) was increased in the liver of E. multilocularis infected mice from 2 months to 6 months.
E. multilocularis metacestode definitely exerts a deep influence on liver homeostasis, by modifying a number of gene expression and metabolic pathways. It especially promotes hepatic cell proliferation, as evidenced by the increased PCNA constantly found in all the experimental time-points we studied and by an increased gene expression of key metabolic pathways.
PLoS ONE 01/2011; 6(1):e14557. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study was undertaken to develop an environmental health indicator for use as a basis for developing preventive measures against cystic (CE) and alveolar (AE) echinococcosis infection in children from rural communities in Xiji County, Ningxia Hui Autonomous Region, P.R. of China. A cross-sectional survey was conducted in 2002 among 861 children under 18 years old. After ultrasound (US) abdominal examination, a questionnaire to identify risk factors for infection (socioeconomic, sanitation and hygiene variables) and collected filter-paper blood samples from each child for specific antibody detections using EmP and EgB antigens. The overall prevalence of echinococcosis by US was 0.1% for CE; no detectable AE was found. The results showed the dog/fox faeces environmental contamination and age-bias behaviour were significant risk factors for both human AE and CE. There was a statistically significant association between both infections and child domicile indicating that infection risk also included geographic independent factors, with the eco-geographic environment being a risk factor for AE and the sociogeographic environment increasing risk for CE. In conclusion, the environmental health indicator, which incorporated the most significant biological, environmental and social factors associated with the risk of echinococcosis infection, can provide clear “warning signals” to decisionmakers for the institution of specific control measures in this Chinese population.