Further CT investigations using contrast enhancement detected a very small hypodense area in the periphery of the calcified herd, which could have harbored a putatively still viable parasitic zone Figure , C. The patient was reexamined by CT at the same time intervals as described above for the other seropositive donors.
No changes in size and morphologic features of the calcified lesion and the peripheral hypodense zone have been demonstrated. The patient received no treatment at any time. The inert lesion was definitively rated as abortive in Nine persons had negative ultrasonography results. One person, however, had a typical hepatic E. Seroprevalence and clinical findings obtained in the present study Table 3 were directly compared with those obtained in a previous study, which had used similar immunodiagnostic tools and blood donor population 6.
Subsequent surgery confirmed the presence of active E. Echinococcosis tests and standard laboratory tools were the same in both studies Conversely, clinical findings CT hepatic lesions compatible with E. Recent findings have clearly documented a persistently high prevalence of E.
These data contrasted to a persistently low annual incidence of AHD 8 to 10 new cases per year in accidentally infected humans 6 , 15 , Until , little information was available about the prevalence of E. In 2 , we reported a focus of high E. The latter represented the highest prevalence ever reported for rodents in central Europe. The discovery and documentation of an area highly endemic for E. Does high endemicity have implications for the rate of infection in domestic animals living near E.
Biology of Obesity: Lessons from Animal Models of Obesity
To address this question, we first had to demonstrate persistence of high endemicity in the rodent population. A 6-year follow-up showed that--independent of interannual fluctuations significant for A. Consequently, the local dog and cat populations hunting rodents were at a persistently high infection risk.
This risk may result in a relatively high exposure risk for human populations in the vicinity. The number of dogs and cats in Switzerland is relatively high approximately , dogs and 1. Local veterinarians assessed the dog and cat populations of our study area as within the Swiss average 1 dog per 10 inhabitants and 1 cat per 5 inhabitants. Therefore, any person in our study area may have had direct contact with pet dogs or cats or may have been to locations contaminated by their feces.
The veterinarians confirmed that dog and cat owners in the study area did not exhibit any peculiarities in comparison to owners in other areas of Switzerland, including the area and period covered by an earlier study 6. As a precaution, all pet owners visiting veterinary practices in the study area were given information on E. The information indicated that carnivores eating rodents in this specific area could be prophylactically treated every 28 days with a therapeutic dose 5 mg per kg body weight of praziquantel.
Biology of Obesity: Lessons from Animal Models of Obesity
Assessment of the effectiveness of this therapeutic regimen will be the topic of a separate study. When we compared our study to other European studies 17 , 18 , we confirmed as a consequence of the persistently high prevalence in intermediate rodent hosts an exceptionally high prevalence of intestinal E. High prevalence among foxes, dogs, cats, and rodents reflects high environmental contamination with E. Thus, we examined the extended exposure risk of the local human population for increases in seroprevalence, by comparing current data with those collected in an earlier study 6.
Higher seroprevalence obtained with the EgHF-ELISA will not be further discussed because the lower specificity of the test may be due to other nonspecific parameters. However, the number of reported clinical cases did not increase. This lack of increase in cases was underlined by the unique detection of one abortive died-out case of AHD first such case documented in Switzerland. Earlier, we had postulated that the time between infection and clinical manifestation was 5 to 15 years 4 , 6. However, we know that, in experimental infections of rodents, seroconversion to the Em2-antigen occurs as early as 4 to 6 weeks after peroral inoculation of E.
As our study covered a 4- to 5-year period of high endemicity to until the human population was assessed, a significant increase in clinical cases, including asymptomatic early cases, which are detectable by ultrasonography, should have been observed in our study.
However, high prevalence of E. Epidemiologic data similar to ours have recently been reported with regard to a rural community in southwestern Germany where a high prevalence of E. Screening of the human population 2, participants found one case of active AHD and nine cases of seropositivity to specific antibodies without detectable liver lesions.
The human population in our study area exhibited low susceptibility to AHD: The relatively high seroprevalence observed in the population was associated with the documented high exposure rate, but the disease rate did not increase. Disease cases included early cases putatively detectable by ultrasonography. In addition to low susceptibility, the persistently low incidence of AHD in our study area may also be accounted for by increased immunity, which may protect a large proportion of infected persons.
For more detailed and definitive conclusions on disease incidence in humans, we will continue to monitor the affected population. A long-term assessment of the same human population is already planned in the Fribourg area over the next 4 to 10 years. By using the same tools as described in this project, it will be possible to document more subtle changes in disease prevalence in humans.
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Berther for excellent veterinary support; S. Maillard for assisting with blood donations; G. Felleisen for organizing blood donations, laboratory samples, and questionnaires; and A. Hemphill for helpful suggestions and critical comments on the manuscript. Table of Contents — Volume 7, Number 3—June Please use the form below to submit correspondence to the authors or contact them at the following address:.
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Emerging Infectious Diseases , 7 3 , Abstract We investigated a focus of highly endemic Echinococcus multilocularis infection to assess persistence of high endemicity in rural rodents, explore potential for parasite transmission to domestic carnivores, and assess serologically putative exposure versus infection frequency in inhabitants of the region. Survey in Intermediate Hosts Rodents The rodent survey has been ongoing since spring Survey in Definitive Hosts Dogs and Cats Three local veterinarians participated in the survey by distributing information and diagnostic fecal containers to dog and cat owners.
Statistical Analyses Comparative statistical analyses of the present seroepidemiologic data and those of a previous study 6 were done with SAS v. Retrospective Statistical Comparative Analyses Seroprevalence and clinical findings obtained in the present study Table 3 were directly compared with those obtained in a previous study, which had used similar immunodiagnostic tools and blood donor population 6.
Protective immune mechanisms against the metacestode of Echinococcus multilocularis. Swiss study of chemotherapy of alveolar echinococcosis--review of a year clinical research project. OLETF rats are hyperphagic beginning several weeks after birth, with increasing body weight eventually progressing to frank obesity [ 46 ]. Hyperinsulinemia is observed beginning at 8 weeks of age, and insulin resistance is observed beginning at 12 weeks of age.
At 25 weeks of age, male OLETF rats display hyperplasia of pancreatic islets, but islets become atrophic by 60 weeks of age [ 46 , 47 ]. Instead, hypertriglyceridemia is found to precede the onset of hyperglycemia and insulin resistance [ 47 ]. OLETF rats are widely used in obesity and diabetes research. There are mouse strain-specific differences in responses to the HFD Table 1 [ 48 ]. Interestingly, within the C57 mouse strain, there are significant differences among substrains in response to the HFD.
Using such high-fat diet-induced obesity mice models, some clues to fight against human obesity have been reported; manipulation of diet may rescue the obesity phenotype even in high-fat-fed condition. BAs have been long recognized as simple lipid solubilizers, however, during the last decades researchers revealed that BAs play pivotal roles in the complex metabolic regulations. Such activation of type 2 deiodinase results in the conversion of thyroxine T4 to triiodothyronine T3 , which enhances energy expenditure [ 51 ].
Furthermore, agonistic compound for TGR5, INT, mimics such metabolic effect of BAs and inhibited the onset of steatosis in high-fat-fed mice [ 52 ]. Furthermore, INT induces incretin effects via the secretion of glucagon-like peptide GLP -1 and therefore ameliorated glucose tolerance [ 52 ].
These researches revealed the potential importance of BAs for the prevention of diet-induced obesity and associated health problem. Interestingly postcholecystectomized patients have been shown to have high prevalence of type 2 diabetes [ 53 ]. Another nutritional intervention method, which could prevent metabolic abnormality, is the diet with high ketogenic essential amino acid KAA such as leucine, isoleucine, valine, lysine, and threonine. Such enhanced administration of high-KAA mixture diet modulated lipid synthetic pathway and prevented hepatic steatosis and insulin resistance with the reduction of body weight under the high-fat diet [ 55 ].
Interestingly such high-KAA mixture has been shown to improve insulin sensitivity in elderly type 2 diabetic subjects [ 56 ]. These reports indicated that the high-fat diet-induced obesity animals could be the good model for the experimental therapy and the translational research to discover a novel therapeutic strategy for obesity epidemic. Obese Monkeys During evolution, primates diverged from rodent lineages about 65—85 million years ago [ 57 ]. In comparison, humans and other great apes Hominoidea diverged from Old World monkeys Cercopithecoidea a relatively recent 25 million years ago [ 58 ].
Obesity models in Old World monkeys, such as macaques, rhesus monkey, and baboons, would therefore provide information relevant to human obesity. When raised in indoor cages, Rhesus monkeys exhibit increased rates of obesity, with some of them developing obesity-associated diseases [ 59 — 61 ]. Captive macaques display obesity in an age-dependent manner when given food ad libitum [ 62 ]. Like humans, these monkeys develop type 2 diabetes and diabetic complications.
It is likely that reduced exercise increases the risk of obesity in these monkeys [ 62 — 64 ]. Spontaneous obesity is also found in wild baboons and in a pedigreed colony [ 65 — 67 ] and occurs in free-ranging rhesus monkeys [ 68 ]. Furthermore, a species of Japanese monkey, Macaca fuscata, develops obesity without frank diabetes [ 69 ].
Genetic models provide useful information about the biology of obesity in humans. This does not mean, however, that these models can provide information on how obesity can cause other health problems. In this section, we introduce several animal models for analyzing human obesity-associated disease pathology. Type 2 diabetes is associated with insulin resistance and is one of the most common metabolic diseases. The incidence of type 2 diabetes has dramatically increased in the past two decades, coinciding with the epidemic of obesity. The pathogenesis of insulin resistance and diabetes-associated complications remains unclear.
Research on type 2 diabetes using animal models of obesity is therefore quite significant. Models of obesity with type 2 diabetes are classified into two categories: Obesity in these models is due to leptin signaling deficiency. These rodent models exhibit microvascular complications similar to humans, such as diabetic retinopathy and nephropathy, and provide important models for testing experimental therapeutics.
Polygenic models of obesity with diabetes may provide more insight to the human condition. Certain inbred strains of mice exhibit remarkable obesity when fed on HFD, whereas others remain lean [ 48 , 49 , 73 ], suggesting gene-diet interactions. Furthermore, some of the strains exhibit obesity with severe insulin resistance and glucose intolerance, whereas others are highly sensitive to insulin-mediated glucose uptake and are resistant to the onset of diabetes Table 1 [ 50 , 74 , 75 ].
In contrast, some strains are very prone to type 2 diabetes but not severely obese. Obesity in humans is associated with the incidence of several cancers.
Likewise, type 2 diabetes has been associated with an increased risk of cancer. Several mechanisms have been proposed to explain the interaction between obesity and cancer development, including the prevalence of type 2 diabetes, increased insulin resistance, elevated levels of insulin-like growth factor 1 IGF-1 , and increased production of sex steroid hormones and adipocytokines [ 76 — 80 ]. However, clear molecular mechanisms that explain obesity-associated cancer have yet to be determined. Recently, Park et al. Furthermore, HFD induced the growth of subcutaneously injected HCC, suggesting that obesity has a systemic effect on tumorigenesis [ 81 ].
With regard to the mechanisms of tumorigenesis in obesity, they found that obesity is associated with increased intracellular transcriptional factor STAT signaling and liver inflammation [ 81 ].
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Metformin belongs to the biguanide class of antitype 2 diabetic drugs. Accumulating evidence suggests that metformin reduces cancer incidence in type 2 diabetic patients. Metformin treatment has been shown to result in a gene expression profile similar to that of long-term caloric restriction [ 87 ], which can reduce the incidence of many age-related diseases, including cancer [ 88 , 89 ].
Metformin treatment inhibits high-energy diet-stimulated colon cancer cell growth [ 90 ] and breast tumor growth in HFD-fed mice but did not inhibit tumor growth in mice fed normal chow [ 91 ]. Although the effects of metformin in obesity-related cancer biology are not clear, these reports suggest that the tumor suppressive effect of metformin may involve the amelioration of a systemic metabolic profile associated with a high-energy diet and obesity.
Elevated leptin levels, often found in obesity, may affect cancer cell growth. Recently, Ribeiro et al. In contrast, Gonzalez et al. Similar leptin-induced proliferation and invasiveness has been shown in endometrial cancer [ 95 ]. The reports regarding the role of leptin in carcinogenesis are still very controversial and require further followup studies.
Obstructive sleep apnea OSA is an important obesity-associated health problem that is characterized by obstruction of the airway and depletion of oxygen tone in the blood. OSA may be associated with the onset of hypertension, diabetes, and coronary heart disease. Although OSA is of clinical importance, the etiology of OSA is not yet clear, perhaps due to the lack of appropriate animal models. The first animal model reported to exhibit sleep apnea was the English bulldog [ 97 ].
These animals exhibit respiration disorders and decreased O 2 saturation that worsen during rapid-eye-movement sleep. Two varieties of obese pigs were also found to be good models of OSA [ 98 , 99 ]. Although these models provide important information about the pathomechanisms of OSA, large-animal-based research is technically difficult.
Therefore, for the development of experimental therapies and drugs, rodent models are superior. In , Van Lunteren et al. Later, this model was found to exhibit sleep apnea syndrome [ ]. ZFRs have since been used for various experimental therapies and have provided important information about OSA [ — ]. Although these dog, pig, and rat models help improve our understanding of the pathophysiology of OSA, mouse models are critical in identifying the genes conferring disease risk [ ]. Recently, NZO mice were used as a model mouse for sleep apnea syndrome [ ].
NZO mice exhibit polygenic obesity and metabolic syndromes, such as insulin resistance, diabetes, hyperlipidemia, and hypertension Table 1 , much like a human sleep apnea patient. This report suggests that the NZO mouse may be a useful model for testing new drugs and experimental therapies for OSA.
Most publications may shed light on the pathology of obesity by forcing HFD or genetic mutations in rodents; however, the conditions are very different from the real problems that humans are facing. The main difference between experimental animal models and human obesity is that humans do not have induced gene mutations and are not forced to eat HFDs. Instead, humans tend to enjoy eating such diets. If we can answer the question of why some individuals prefer to eat high-fat food and others do not, we would have a direct solution for obesity.
Little evidence is currently available on this topic, but some seminal results have been shown [ , ].