Neglected Parasitic Infections: What Family Physicians Need to Know-A CDC Update.

Chagas disease, cysticercosis, and toxoplasmosis affect millions of people in the United States and are considered neglected parasitic diseases. Few resources are devoted to their surveillance, prevention, and treatment. Chagas disease, transmitted by kissing bugs, primarily affects people who have lived in Mexico, Central America, and South America, and it can cause heart disease and death if not treated. Chagas disease is diagnosed by detecting the parasite in blood or by serology, depending on the phase of disease. Antiparasitic treatment is indicated for most patients with acute disease. Treatment for chronic disease is recommended for people younger than 18 years and generally recommended for adults younger than 50 years. Treatment decisions should be individualized for all other patients. Cysticercosis can manifest in muscles, the eyes, and most critically in the brain (neurocysticercosis). Neurocysticercosis accounts for 2.1% of all emergency department visits for seizures in the United States. Diagnosing neurocysticercosis involves serology and neuroimaging. Treatment includes symptom control and antiparasitic therapy. Toxoplasmosis is estimated to affect 11% of people older than six years in the United States. It can be acquired by ingesting food or water that has been contaminated by cat feces; it can also be acquired by eating undercooked, contaminated meat. Toxoplasma infection is usually asymptomatic; however, people who are immunosuppressed can develop more severe neurologic symptoms. Congenital infection can result in miscarriage or adverse fetal effects. Diagnosis is made with serologic testing, polymerase chain reaction testing, or parasite detection in tissue or fluid specimens. Treatment is recommended for people who are immunosuppressed, pregnant patients with recently acquired infection, and people who are immunocompetent with visceral disease or severe symptoms.

Mathematical model of the life cycle of taenia-cysticercosis: transmission dynamics and chemotherapy (Part 1).

BACKGROUND: Taenia solium is the aetiological agent of human taeniasis, pig cysticercosis and human neurocysticercosis, which are serious public health problems, especially in developing countries. METHODS: A mathematical model of the transmission dynamics of taeniasis-cysticercosis is formulated. The model consists of a coupled system of differential equations, which are density-dependent equations for describing the flow of the parasite through the life cycle. The model is hybrid since it comprises deterministic equations with stochastic elements which describe changes in the mean parasite burden and incorporates the overall pattern of the parasites' distribution. RESULTS: Sensitivity and bifurcation analyses were carried out to determine the range of values of the model. The model can reproduce the observed epidemiological patterns of human taeniasis, pig and human cysticercosis. For example, for a wide range of parameter values, the mean intensity of adult worms tends to rapidly stabilize in one parasite per individual host. From this model, we also derived a Susceptible-Infected model to describe the prevalence of infection in humans and pigs. Chemotherapeutic interventions against pig cysticercosis or human taeniasis may reduce rapidly and effectively the mean intensity of human taeniasis, pig cysticercosis and human cysticercosis. This effect can be achieved even if the protective efficacy of the drug is of the order of 90% and the coverage rate is 90%. This means that health in humans infected either with adult worms or cysticerci may be achieved by the application of anthelmintic drugs against pig cysticercosis. However, treatment against human cysticercosis alone, does not influence neither human teniasis nor pig cysticercosis. This is because human cysticercosis infection does not influence the value of the basic reproductive number (Ro). CONCLUSIONS: Even coverage of 100% in the administration of anthelmintics did not eliminate the infection. Then elimination of the infection in all hosts does not seem a feasible goal to achieve by administering only chemotherapeutic interventions. Throughout the manuscript a discussion of our model in the context of other models of taeniasis-cysticercosis is presented.

Helminth infection alters mood and short-term memory as well as levels of neurotransmitters and cytokines in the mouse hippocampus.

UNLABELLED: Helminthic infections are important causes of morbidity and mortality in many developing countries, where children bear the greatest health burden. The ability of parasites to cause behavioral changes in the host has been observed in a variety of host-parasite systems, including the Taenia crassiceps-mouse model. In murine cysticercosis, mice exhibit a disruption in the sexual, aggressive and avoidance predator behaviors. OBJECTIVE: The present study was conducted to characterize short-term memory and depression-like behavior, as well as levels of neurotransmitters and cytokines in the hippocampus of cysticercotic male and female mice. METHODS: Cytokines were detected by RT-PCR and neurotransmitters were quantified by HPLC. RESULTS: Chronic cysticercosis infection induced a decrease in short-term memory in both male and female mice, having a more pronounced effect in females. Infected females showed a significant increase in forced swimming tests with a decrease in immobility. In contrast, male mice showed an increment in total activity and ambulation tests. Serotonin levels decreased by 30% in the hippocampus of infected females whereas noradrenaline levels significantly increased in infected males. The hippocampal expression of IL-4 increased in infected female mice, but decreased in infected male mice. CONCLUSION: Our study suggests that intraperitoneal chronic infection with cysticerci in mice leads to persistent deficits in tasks dependent on the animal's hippocampal function. Our findings are a first approach to elucidating the role of the neuroimmune network in controlling short-term memory and mood in T. crassiceps-infected mice.

Unusual and Rare Causes of Monocular Elevation Deficit.

INTRODUCTION: To study the rare and unusual causes of monocular elevation deficit. METHODS: Five patients presenting to us with diplopia and elevation deficit were thoroughly examined and were found to have monocular elevation deficit due to rare causes. OBSERVATIONS: All five were found to have different underlying etiologies - iatrogenic, sphenoid wing meningioma, cysticercosis, sarcoidosis and mid brain infarct, and were managed appropriately. DISCUSSION: Monocular Elevation Deficit can occur due to a variety of causes. Having a high index of suspicion for the more serious etiologies is of utmost importance. Thorough clinical examination and imaging help clinch the diagnosis.

Transcriptome profiling of Cysticercus Pisiformis provides insight into responses to host bile acids.

Bile acids in host intestine activate larvae of tapeworms and facilitate its invasion. However, the mechanism underlying this process is poorly understood. In order to better understand responses of tapeworms to host biles, we used RNA-Seq profiling method to study the transcriptomes of Cysticercus Pisiformis (larvae of Taenia Pisiformis) after host bile acid treatment. A total of 338.32 million high-quality clean reads were obtained by Illumina Hiseq platform. Totally, 62,009 unigenes were assembled, 38,382 of which were successfully annotated to known databases. A total of 9324 unigenes were identified as differentially expressed genes (DEGs), of which 5380 and 3944 genes were up- and down-regulated in the group treated with bile acids, respectively. Gene Ontology analysis revealed that biosynthesis and energy metabolism potential were significantly strengthened after host bile treatment in C. pisiformis. Similarly, KEGG pathway analysis revealed an enrichment of pathways related to lipid metabolism and carbohydrate metabolism. Among them, 'AMPK signaling pathway' which is critical in balancing cellular energy, was significantly enriched after bile acids activation. In addition, pathways of 'Fatty acid biosynthesis', 'Fatty acid elongation', 'Starch and sucrose metabolism', and 'glycolysis gluconeogenesis' were also significantly changed after bile acid treatment. qRT-PCR analysis confirmed the differential abundances of some key genes in these pathways. Our data suggest that host bile acids remarkably promote the pathways of energy metabolism of this parasite and regulate the genes involved in balancing lipid metabolism and carbohydrate metabolism. These findings provide new insights on the lifecycle of Taenia parasites.

Neonatal exposure to estradiol induces resistance to helminth infection and changes in the expression of sex steroid hormone receptors in the brain and spleen in adult mice of both sexes.

A single injection of 17beta-estradiol administered to 4-day-old male and female mice increased the cellular immune response, and induced resistance to Taenia crassiceps cysticercosis as well as changes in the expression pattern of progesterone (PR) and estrogen receptor (ER) isoforms in the brain and splenocytes. Regardless of gender, when treated mice reached adulthood, they were highly resistant to infection. Female mice presented early vaginal opening and altered estrous cycles. In male and female mice, the expression of the PR and ER isoforms in the brain was differentially regulated after neonatal exposure to estradiol. Moreover, an increase in the expression of IL-4 and IFN-gamma was found in the serum of experimentally infected neonatally estrogenized animals, which correlated with the observed protection against T. crassiceps infection. In conclusion, early exposure to estradiol permanently modifies immune system activity and sex steroid hormone receptors in the brain, and causes profound changes in sex-associated susceptibility, leading to resistance to helminth parasite infection.

Toxocariasis/cysticercosis seroprevalence in a long-term rural settlement, São Paulo, Brazil.

Seroprevalence of Toxocara and Taenia solium and risk factors for infection with these parasites were explored in a long-term rural settlement in São Paulo state, Brazil. An ELISA for the detection of anti-Toxocara IgG and IgE and anti-T. solium cysticerci was standardized using Toxocara excretory-secretory antigens (TES) obtained from the cultured second-stage larvae of T. canis and by vesicular fluid antigen from Taenia crassiceps cysticerci (VF). For cysticercosis, the reactive ELISA samples were assayed by Western blot using 18 kDa and 14 kDa proteins purified from VF. Out of 182 subjects, 25 (13.7%) presented anti-Toxocara IgG and a positive correlation between total IgE and the reactive index of specific anti-TES IgE (P=0.0265) was found amongst the subjects found seropositive for anti-Toxocara IgG. In these individuals 38.0% showed ocular manifestations. The frequency of anti-T. solium cysticerci confirmed by Western blot was 0.6%. Seropositivity for Toxocara was correlated with low educational levels and the owning of dogs. Embryonated eggs of Toxocara spp. were found in 43.3% of the analysed areas.

Influence of the interaction between cysticercosis and obesity on rabbit behavior and productive parameters.

Parasites induce behavioral changes in the host and obesity is a health problem affecting different animal species. Cysticercosis caused by Taenia pisiformis affects some behavior of rabbits and reproductive behavior of does. Rabbits do not escape from metabolic disorders, being long-live animals useful in breeding, research and companion animals. Here, we addressed the interaction between parasitosis and obesity, and studied how these conditions or the comorbidity affect behavioral and productive parameters in bucks infected with 3000 T. pisiformis eggs. We found that the chronic infection reduced locomotor activity by 28.5% in obese, 18.5% in infected and 47% in obese-infected group (comorbid). The exploratory activity reduced by 42% in obese, 48% in infected and 68% in comorbid rabbits (P ≤ 0.001). Chinning was not affected by obesity, while infection decreased it by 25%. Behavioral reproductive parameters like response time, the mount latency and number of ejaculates were affected by infection and obesity. Furthermore, obesity seems to increase the parasite load promoting the formation of liver granulomas (16% granulomas compared with normal weight), with a higher number of cysticerci in obese animals (86% more than normal weight). Infection decreases body weight, body mass index and the zoometric index BW/LV in obese and normal weight rabbits. In conclusion, infection with T. pisiformis altered behavioral and productive parameters, and obesity magnifies the impact caused by the infection. Also, obesity leads to major susceptibility to infection with T. pisiformis.

Historical perspective: The British contribution to the understanding of neurocysticercosis.

Neurocysticercosis, or brain infestation with the larval stage of Taenia solium, is the most common risk factor for epilepsy in many endemic regions of the world. Hardly any cases are seen in Western developed countries, including Britain. However, a sizeable number (n = 450) was seen among British soldiers returning from deputation to India, then a British colony, first reported by Col. MacArthur at the Queen Alexandria Military Hospital in 1931. Here, we review the influence of the perceptive observations of British Army medics on the understanding of the parasitic disorder. The majority of these people presented with epilepsy. Among the contributions of the army medics were establishing the diagnosis, initially by histological examination of subcutaneous and muscular infestation, and later by radiography, clarifying the prognosis and the role of medical and surgical treatments and uncovering the close relationship between the larval (cysticercosis) and adult (intestinal tapeworm) stages of T. solium.

Impact of naturally acquired Taenia solium cysticercosis on the hormonal levels of free ranging boars.

In chronically infected BALBc/AnN male mice, Taenia crassiceps cysticercosis induces changes in the host's sex steroids hormone that lead to their estrogenization and deandrogenization, with possible repercussions on their susceptibility to infections. Here reported are the serum steroid levels in free range cysticercotic male boars. Therefore, the possible effects of Taenia solium cysticerci over the pig steroid levels were evaluated. Herein are described the sex steroids and cortisol levels of non-cysticercotic (n=25) and cysticercotic (n=22) adult boars, as diagnosed by tongue inspection, all free-ranging in a typical village of an endemic rural area in Mexico. A significant reduction of testosterone (P=0.022) and a likely one of 17beta-estradiol (P=0.08) levels were found in the cysticercotic boars in comparison with those non-cysticercotic, whilst no significant differences in the cortisol and DHEA levels were detected. Serum levels of specific antibodies did not correlate with infection nor with the levels of any of the hormones measured. Results suggest that T. solium cysticercosis significantly affects the hormonal status of its porcine host independently of their antibody response.

Balb/Cj male mice do not feminize after infection with larval Taenia crassiceps.

Balb/cJ mice fail to mount an immune response capable of clearing infection with larval Taenia crassiceps. Additionally, male Balb/cJ mice display a lag in larval growth of approximately 3 wk as compared to growth in female mice. It has been reported that male Balb/ cAnN mice generate a protective immune response early in infection, and become permissive to larval growth after they feminize (200-fold increase in serum estradiol and 90% decrease in serum testosterone). To determine if a different strain of Balb/c mice (Balb/cJ) also feminize, serum was collected from infected male mice for 16 wk and levels of 17-beta-estradiol and testosterone were measured via ELISA. In addition, the mounting responses of 12- and 16-wk infected male mice, as well as uninfected control mice, were determined after isolation with a female mouse. The results of these experiments show that male Balb/cJ mice do not feminize during infection with larval T. crassiceps. There was no significant change in serum levels of either 17-beta-estradiol or testosterone during the course of infection (> 16 wk). Moreover, there was no significant decrease in the number of times infected male mice mounted the female mouse as compared to uninfected controls. These results suggest that there may be variances between the substrains of Balb/c mice that lead to the phenotypic differences reported for male Balb/cJ and Balb/cAnN mice.

Substance P is associated with heart enlargement and apoptosis in murine dilated cardiomyopathy induced by Taenia crassiceps infection.

Dilated cardiomyopathy (degeneration of heart muscle and heart enlargement) is an important cause of heart failure among young adults. Dilated cardiomyopathy may be a complication during or after various viral, bacterial, or parasitic diseases. Substance P (SP) is a neurotransmitter that is involved in the pathogenesis of various diseases. To determine whether SP is associated with cardiac changes in murine cysticercosis, we compared heart-weight to body-weight ratio, cardiac pathology, cardiomyocyte size, and cardiac-apoptosis (TUNEL assay) in hearts from Taenia crassiceps-infected (wild-type vs. SP-knockout) mice. We noted that, as compared with control uninfected wild-type mice, elevated protein levels of SP and its receptor as studied by ELISA or immunohistochemistry, respectively, were elevated in the hearts of parasite-infected wild-type mice. The heart-weight to body-weight ratios were significantly higher in the parasite-infected wild-type mice versus those of the infected SP-knockout mice. Furthermore, wild-type infected mice developed dilated cardiomyopathy with increased chamber size of both ventricles, decreased ventricular wall thickness, compensatory cardiomyocyte hypertrophy, and increased cardiac apoptosis. This cardiac pathology did not develop in mice lacking SP activity (i.e., in infected SP knockout mice) or in uninfected mice. These data indicate that SP is associated with cardiac changes in an animal model of parasitic dilated cardiomyopathy.

Short report: Evidence and potential for transmission of human and swine Taenia solium cysticercosis in the Piracuruca region, Piauí, Brazil.

The study conducted in the Cocal dos Alves municipality, located in the Piracuruca region of Piauí State, Brazil in November of 2003 was based on both a socio-behavioral survey and analysis of serum antibodies and parasitic materials. Pig raising is the main economic activity with 91.4% using extensive farming. On the studied population, 54.3% of people did not apply any sanitary measures to wastewater, 45.7% used septic tanks, and 69.1% consumed water without treatment. The data collected indicated the occurrence and active transmission of the taeniasis-cysticercosis complex in the region. One of seven voluntary persons was positive in antibody-ELISA tests using both native and recombinant antigens. Multiplex PCR and DNA sequencing of cyst samples obtained from a pig revealed the presence of the Afro-American genotype of Taenia solium. This study revealed the occurrence of human and porcine cysticercosis in the Piracuruca region of Piauí State, middle-north of Brazil.

Usefulness of severe combined immunodeficiency (scid) and inbred mice for studies of cysticercosis and echinococcosis.

The topics in this review are the usefulness of immunodeficient and inbred mice for studies of developmental biology, drug efficacy and host specificity in cysticercosis and echinococcosis. In non-obese diabetic severe combined immunodeficiency (NOD/Shi-scid) mice of both sexes, in vitro hatched oncospheres of all three human taeniid species (Taenia solium, Taenia saginata and Taenia asiatica) developed into cysticerci comparable to or bigger than those developed in their known intermediate host animals, whereas only females were susceptible to these infections in other scid mice of BALB/c, C57BL or C.B-17 inbred strains. Detailed morphological observation from post-oncospheral to cysticercus developmental stages is expected to be easy when we use NOD/Shi-scid mice experimentally inoculated with in vitro hatched oncospheres. Metacestocidal effect of oxfendazole was evaluated in NOD/Shi-scid mice experimentally inoculated with oncospheres of T. solium. In Echinococcus multilocularis infection, larval tissue proliferated without induction of inflammatory host responses in scid mice, thus facilitating isolation of the larval vesicles and protoscoleces for biochemical and molecular biological studies. Trans portal inoculation of metacestode tissues resulted in proliferation of secondary echinococcal foci localized exclusively in the liver without metastasis to other tissues or organs. The advantages of a mouse model for Echinococcus granulosus are also described.

Proinflammatory cytokines in granulomas associated with murine cysticercosis are not the cause of seizures.

Neurocysticercosis is a parasitic infection of the human central nervous system caused by the cestode Taenia solium. The most common clinical manifestations of neurocysticercosis are seizures. Taenia crassiceps cysticercosis in mice has been used as an experimental model for T. solium cysticercosis. Granulomas surrounding murine cysticerci have striking immunopathological resemblance to human neurocysticercosis; early stage granulomas were able to induce seizures in a rodent model. To assess the role of proinflammatory cytokines in early stage granulomas, we isolated RNA from murine cysticercal granulomas and checked for cytokine expression by reverse transcriptase-polymerase chain reaction (RT-PCR) and/or ribonuclease (RNase) protection assays. Cytokine expression was compared with histological stages. Interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist, and tumor necrosis factor (TNF-alpha) were the major cytokines detected in all granulomas. Signals for IL-12, IL-18, and IL-6 RNA were not consistently detected and, when detected, were barely demonstrable. Expression of migration inhibitory factor (MIF), IL-6, IL-1alpha, TNF-alpha, and IL-18 was not significantly different between early and late-stage granulomas. Expression of IL-1beta, IL-1 receptor antagonist, and IL-12 p40 were higher in late, compared with early, stages. Thus, we demonstrated a broad range of cytokines in these granulomas. However, we did not document preferential expression of any proinflammatory cytokines in early stage granulomas. Thus, proinflammatory cytokines are not responsible for the seizures in the rodent model of neurocysticercosis.

Elucidating the influence of praziquantel nanosuspensions on the in vivo metabolism of Taenia crassiceps cysticerci.

The aim of this work was to develop nanosuspensions of praziquantel (PZQ) and to evaluate their influence on the energetic metabolism of cysticerci inoculated in BALB/c mice. We analyzed metabolic alterations of glycolytic pathways and the tricarboxylic acid cycle in the parasite. The nanosuspensions were prepared by precipitation and polyvinyl alcohol (PVA), poloxamer 188 (P188) and poloxamer 407 (P407) were used as stabilizers. Nanosuspension prepared with PVA had a particle size of 100nm, while P188- and P407-based nanosuspensions had particle sizes of 74nm and 285nm, respectively. The zeta potential was -8.1, -8.6, and -13.2 for the formulations stabilized with PVA, P188 and P407, respectively. Treatments of T. crassiceps cysticerci-infected mice resulted in an increase in glycolysis organic acids, and enhanced the partial reversion of the tricarboxylic acid cycle, the urea cycle and the production of ketonic bodies in the parasites when compared to the groups treated with conventional PZQ. These data suggest that PZQ nanosuspensions greatly modified the energetic metabolism of cysticerci in vivo. Moreover, the remarkable metabolic alterations produced by the stabilizers indicate that further studies on nanoformulations are required to find potentially suitable nanomedicines.

Neurocysticercosis.

Cysticercosis is an infection caused by Taenia solium larvae (cysticerci). When the cysticercus is lodged in the central nervous system (CNS), the disease is known as neurocysticercosis (NCC). NCC is the most frequent and most widely disseminated human neuroparasitosis. It is endemic in many parts of the world, particularly Latin America, Africa, and Asia, and still relatively frequent in Portugal, Spain and Eastern European countries It is also endemic in developed countries with high rates of immigration from endemic areas. Man may act as an intermediate host after ingestion of mature, viable T. solium eggs via the fecal-oral route. The development of lesions in the brain and leptomeninges, and the consequent of onset of symptoms associated with NCC are mainly due to the host immune-inflammatory response. As long as the cysticercus remains viable, there is relative host immune tolerance. It is only when the parasite dies that massive antigen exposure occurs, with intensification of the immune response/inflammatory reaction and the appearance or worsening of symptoms. NCC can be asymptomatic or cause widely varied clinical manifestations, such as seizures, increased intracranial pressure, ischemic cerebrovascular disease, dementia, and signs of compression of the spinal roots/cord. The combination of two or more symptoms is common. Such clinical polymorphism is determined by 1) the number of lesions (single or multiple cysticerci); 2) the location of CNS lesions (subarachnoid, intracerebral, intraventricular, intramedullary); 3) the type of cysticercus (Cysticercus cellulosae, Cysticercus racemosus); 4) the stage of development and involution of the parasite (vesicular or viable, necrotic, fibrocalcified nodule); and 5) the intensity of the host immune-inflammatory response (no inflammatory reaction, leptomeningitis, encephalitis, granular ependymitis, arteritis).

CNS cysticercosis.

Worldwide, cysticercosis is the most common CNS parasite. Because of immigration from endemic areas, cysticercosis has become more common in the United States. Seventeen cases have been seen at the University of California Medical Center, San Diego (La Jolla) over the last ten years. Eight patients had intracranial hypertension; three, seizures; three, intracranial hypertension; and seizures; two, strokes; and one, retinal involvement. Diagnosis was by surgical biopsy in five cases and by clinical setting plus positive serologic findings in 12. Twelve patients underwent surgical procedures during their illness, one patient died, and five improved with steroid therapy. Clinical, serologic, and pathologic criteria permit definitive diagnosis. Therapy is currently directed toward complications of the primary infection, which usually is inactive at the time of presentation.