Olfactory modulation of the medial prefrontal cortex circuitry: Implications for social cognition.

Olfactory dysfunction is manifested in a wide range of neurological and psychiatric diseases, and often emerges prior to the onset of more classical symptoms and signs. From a behavioral perspective, olfactory deficits typically arise in conjunction with impairments of cognition, motivation, memory, and emotion. However, a conceptual framework for explaining the impact of olfactory processing on higher brain functions in health and disease remains lacking. Here we aim to provide circuit-level insights into this question by synthesizing recent advances in olfactory network connectivity with other cortical brain regions such as the prefrontal cortex. We will focus on social cognition as a representative model for exploring and critically evaluating the relationship between olfactory cortices and higher-order cortical regions in rodent models. Although rodents do not recapitulate all dimensions of human social cognition, they have experimentally accessible neural circuits and well-established behavioral tests for social motivation, memory/recognition, and hierarchy, which can be extrapolated to other species including humans. In particular, the medial prefrontal cortex (mPFC) has been recognized as a key brain region in mediating social cognition in both rodents and humans. This review will highlight the underappreciated connectivity, both anatomical and functional, between the olfactory system and mPFC circuitry, which together provide a neural substrate for olfactory modulation of social cognition and social behaviors. We will provide future perspectives on the functional investigation of the olfactory-mPFC circuit in rodent models and discuss how to translate such animal research to human studies.

Taenia martis Neurocysticercosis-Like Lesion in Child, Associated with Local Source, the Netherlands.

A neurocysticercosis-like lesion in an 11-year-old boy in the Netherlands was determined to be caused by the zoonotic Taenia martis tapeworm. Subsequent testing revealed that 15% of wild martens tested in that region were infected with T. martis tapeworms with 100% genetic similarity; thus, the infection source was most likely local.

Molecular Confirmation of Taenia solium Taeniasis in Child, Timor-Leste.

We report a case of Taenia solium taeniasis in a 10-year-old child in Timor-Leste, confirmed by molecular analysis, suggesting T. solium transmission to humans is occurring in Timor-Leste. Proactive measures are needed to improve public understanding of prevalence, geographic spread, and health implications of human taeniasis and cysticercosis in Timor-Leste.

Neurocysticercosis: The duration of its preclinical phase relies on the parasite location.

OBJECTIVES: Neurocysticercosis (NC) is a heterogeneous disease particularly in terms of response to treatment and prognosis. Parasite localization is one of the main factors involved in this heterogeneity. In this study we aim to determine whether differences in the duration of the preclinical phase associated with parasite location, could contribute to said heterogeneity. METHODS: Ninety-nine patients were included, 24 with parasites in the parenchyma (PAR), 56 in the subarachnoid (SA) space and 19 in the ventricular system (IV). A questionnaire designed to assess exposure to classic NC risk factors 5, 10, 15, 20 and more than 20 years prior to diagnosis was applied. The results were compared between the three groups. Also, asymptomatic relatives of patients who had shared their living conditions in childhood or more recently were included and underwent brain scan and blood testing for specific antibodies. RESULTS: Over the course of their lives, exposure to risk factors decreased significantly for all patients, although the decrease was more evident in patients with parasites in the SA space (p < 0.001) compared to patients with PAR (p = 0.011) or IV cysts (p = 0.020). Five years prior to diagnosis, exposure to risk factors was significantly higher in patients with PAR or IV NC than in patients with SA NC (p = 0.04). Furthermore, individuals in close contact with PAR or IV patients in the years preceding diagnosis were more likely to have asymptomatic NC, specific antibodies in sera, particularly IgM, compared to individuals in close contact with SA patients during the same period. CONCLUSIONS: All these findings are highly suggestive of the possibility of a more recent infection of patients affected by parenchymal and ventricular NC than of patients with subarachnoid NC. Consequently, subarachnoid disease could be considered a chronic disease, which, probably contributes to the severity of the disease as well as the minimal response to medical treatment.

Mass Spectrometry Identifies Taenia solium Proteins in Sera of Patients With and Without Parenchymal Neurocysticercosis.

Neurocysticercosis (NCC), a major cause of global acquired epilepsy, results from Taenia solium larval brain infection. T. solium adult worms release large numbers of infective eggs into the environment contributing to high levels of exposure in endemic areas. This study identifies T. solium proteins in the sera of individuals with and without NCC using mass spectrometry to examine exposure in endemic regions. Forty-seven patients (18-51 years), 24 parenchymal NCC (pNCC), 8 epilepsy of unknown aetiology, 7 glioma, 8 brain tuberculoma, and 7 healthy volunteers were studied. Trypsin digested sera were subject to liquid chromatography-tandem mass spectrometry and spectra of 375-1700 m/z matched against T. solium WormBase ParaSite database with MaxQuant software to identify T. solium proteins. Three hundred and nineteen T. solium proteins were identified in 87.5% of pNCC and 56.6% of non-NCC subjects. Three hundred and four proteins were exclusive to pNCC sera, seven to non-NCC sera and eight in both. Ten percent, exhibiting immune-modulatory properties, originated from the oncosphere and cyst vesicular fluid. In conclusion, in endemic regions, T. solium proteins are detected in sera of individuals with and without pNCC. The immunomodulatory nature of these proteins may influence susceptibility and course of infection.

Helminthic dehydrogenase drives PGE2 and IL-10 production in monocytes to potentiate Treg induction.

Immunoregulation of inflammatory, infection-triggered processes in the brain constitutes a central mechanism to control devastating disease manifestations such as epilepsy. Observational studies implicate the viability of Taenia solium cysts as key factor determining severity of neurocysticercosis (NCC), the most common cause of epilepsy, especially in children, in Sub-Saharan Africa. Viable, in contrast to decaying, cysts mostly remain clinically silent by yet unknown mechanisms, potentially involving Tregs in controlling inflammation. Here, we show that glutamate dehydrogenase from viable cysts instructs tolerogenic monocytes to release IL-10 and the lipid mediator PGE2 . These act in concert, converting naive CD4+ T cells into CD127- CD25hi FoxP3+ CTLA-4+ Tregs, through the G protein-coupled receptors EP2 and EP4 and the IL-10 receptor. Moreover, while viable cyst products strongly upregulate IL-10 and PGE2 transcription in microglia, intravesicular fluid, released during cyst decay, induces pro-inflammatory microglia and TGF-ß as potential drivers of epilepsy. Inhibition of PGE2 synthesis and IL-10 signaling prevents Treg induction by viable cyst products. Harnessing the PGE2 -IL-10 axis and targeting TGF-ß signaling may offer an important therapeutic strategy in inflammatory epilepsy and NCC.

Environmental distribution of Echinococcus- and Taenia spp.-contaminated dog feces in Kyrgyzstan.

Recently, there have been epidemics of human cystic echinococcosis (CE) and alveolar echinococcosis (AE) in Kyrgyzstan. This study investigated 2 districts for the presence of Echinococcus granulosus s.l. and Echinococcus multilocularis eggs; species identity was confirmed by polymerase chain reaction in dog feces and the level of environmental contamination with parasite eggs in 2017­2018 was also investigated. In the Alay district 5 villages with a high reported annual incidence of AE of 162 cases per 100 000 and 5 villages in the Kochkor district which had a much lower incidence of 21 cases per 100 000 were investigated. However, the proportion of dog feces containing E. granulosus s.l. eggs was ~4.2 and ~3.5% in Alay and Kochkor respectively. For E. multilocularis, the corresponding proportions were 2.8 and 3.2%. Environmental contamination of Echinococcus spp. eggs was estimated using the McMaster technique for fecal egg counts, weight and density of canine feces. The level of environmental contamination with E. multilocularis eggs was similar at 4.4 and 5.0 eggs per m2 in Alay and Kochkor respectively. The corresponding values for E. granulosus s.l. were 8.3 and 7.5 eggs per m2. There was no association between village or district level incidence of human AE or CE and the proportion of dog feces containing eggs of Echinococcus spp. or the level of environmental contamination. Increased contamination of taeniid eggs occured in the autumn, after the return of farmers with dogs from summer mountain pastures.

Global profiling of miRNA and protein expression patterns in rabbit peritoneal macrophages treated with exosomes derived from Taenia pisiformis cysticercus.

Infection of Taenia pisiformis cysticercus is very frequently found in lagomorphs and causes serious economic losses to rabbit breeding industry. T. pisiformis cysticercus has evolved numerous strategies to manipulate their hosts. The release of exosomes is of importance in the interaction between host and parasite. However, the mechanism by which T. pisiformis cysticercus evades the host immune system for long-term survival within the host remains unclear. Using small RNA sequencing and TMT labelling proteomic, we profiled the expression patterns of miRNAs and proteins in rabbit peritoneal macrophages treated with T. pisiformis cysticercus exosomes. Seven differentially expressed (DE)-miRNAs and six DE-proteins were randomly selected to validate the accuracy of the sequencing data by qRT-PCR or western blot. Functions of DE-miRNAs and proteins were analyzed using public data bases. And DE-miRNAs-DE-proteins correlation network were established. CCK-8 assay was used to evaluate the effect of exosomes on macrophages proliferation. Cell cycle of macrophages, isolated from T. pisiformis-infected rabbits, was determined using flow cytometry. A total of 21 miRNAs were significantly differentially expressed, including three worm-derived miRNAs. The expressions of miRNAs and proteins were consistent with the sequencing results. DE-miRNAs targets were related to cell proliferation and apoptosis. Exosomes treatment resulted in a decrease of macrophages proliferation. In vivo, T. pisiformis cysticercus significantly induced S phase cell arrest. Moreover, DE-proteins were related to production of interferon-gamma and interleukin-12, and immunoregulation. Correlation network analysis revealed a negative correlation relationship between DE-miRNAs and DE-proteins. Among them, novel334 and tpi-let-7-5p have potential regulatory effects on IL1ß and NFκB2 respectively, which imply that novel334-IL1ß/tpi-let-7-5p-NFκB2 axis may be an important way that T. pisiformis cysticercus modulates host immune response through exosomes. Further understanding of these potential regulatory mechanisms will contribute to clarify the mechanism of escape mediated by T. pisiformis exosomes.

Effect of Hydroxyurea on Morphology, Proliferation, and Protein Expression on Taenia crassiceps WFU Strain.

Flatworms are known for their remarkable regenerative ability, one which depends on totipotent cells known as germinative cells in cestodes. Depletion of germinative cells with hydroxyurea (HU) affects the regeneration of the parasite. Here, we studied the reduction and recovery of germinative cells in T. crassiceps cysticerci after HU treatment (25 mM and 40 mM of HU for 6 days) through in vitro assays. Viability and morphological changes were evaluated. The recovery of cysticerci's mobility and morphology was evaluated at 3 and 6 days, after 6 days of treatment. The number of proliferative cells was evaluated using EdU. Our results show morphological changes in the size, shape, and number of evaginated cysticerci at the 40 mM dose. The mobility of cysticerci was lower after 6 days of HU treatment at both concentrations. On days 3 and 6 of recovery after 25 mM of HU treatment, a partial recovery of the proliferative cells was observed. Proteomic and Gene Ontology analyses identified modifications in protein groups related to DNA binding, DNA damage, glycolytic enzymes, cytoskeleton, skeletal muscle, and RNA binding.

Variation of the 2D Pattern of Brain Proteins in Mice Infected with Taenia crassiceps ORF Strain.

Some parasites are known to influence brain proteins or induce changes in the functioning of the nervous system. In this study, our objective is to demonstrate how the two-dimensional gel technique is valuable for detecting differences in protein expression and providing detailed information on changes in the brain proteome during a parasitic infection. Subsequently, we seek to understand how the parasitic infection affects the protein composition in the brain and how this may be related to changes in brain function. By analyzing de novo-expressed proteins at 2, 4, and 8 weeks post-infection compared to the brains of the control mice, we observed that proteins expressed at 2 weeks are primarily associated with neuroprotection or the initial response of the mouse brain to the infection. At 8 weeks, parasitic infection can induce oxidative stress in the brain, potentially activating signaling pathways related to the response to cellular damage. Proteins expressed at 8 weeks exhibit a pattern indicating that, as the host fails to balance the Neuro-Immuno-Endocrine network of the organism, the brain begins to undergo an apoptotic process and consequently experiences brain damage.

Visceral cysticercosis in a Kunekune sow: description and molecular identification of Taenia hydatigena.

A 2-year-old Kunekune sow was submitted for necropsy following death after peritonitis and sepsis. In addition to peritonitis, numerous fluid-filled cysts were identified in the mesentery and hepatic parenchyma, which contained an approximately 1 cm metacestode (cysticercosis). Subsequent molecular characterization confirmed the presence of Taenia hydatigena, a non-zoonotic cestode species. To our knowledge, visceral cysticercosis caused by T. hydatigena has not been previously documented in Kunekune pigs. Taenia solium is a differential diagnosis of public health importance in cases of cysticercosis. Although Taenia solium is not commonly reported nor endemic in the United States, its zoonotic potential warrants consideration in the initial diagnostic assessment. Clinicians should be aware of the presence of T. hydatigena in its definitive and intermediate hosts.

Effect of old age on the subpopulations of enteric glial cells in human descending colon.

Old age is associated with a higher incidence of lower bowel conditions such as constipation. Recent evidence suggest that colonic motility may be influenced by enteric glial cells (EGCs). Little is known about the effect of aging on the subpopulation of EGCs in the human colon. We assessed and compared the pattern of distribution of EGCs in adult and elderly human colon. Human descending colon were obtained from 23 cancer patients comprising of adults (23-63 years; 6 male, 7 female) and elderly (66-81 year; 6 male, 4 female). Specimens were serially-sectioned and immunolabeled with anti-Sox-10, anti-S100 and anti-GFAP for morphometric analysis. Standardized procedures were utilized to ensure unbiased counting and densitometric evaluation of EGCs. The number of Sox-10 immunoreactive (IR) EGCs were unaltered with age in both the myenteric plexus (MP) (respectively, in adult and elderly patients, 1939 ± 82 and 1760 ± 44/mm length; p > .05) and submucosal plexus; there were no apparent differences between adult males and females. The density of S100-IR EGCs declined among the elderly in the circular muscle and within the MP per ganglionic area. In the adult colon, there were more S100-IR EGCs distributed in the circular muscle per unit area than the Taenia coli. There was little or no GFAP-IR EGCs in both adult and elderly colon. We concluded that aging of the human descending colon does not result in a loss of Sox-10-IR EGCs in the MP and SMP but reduces S100-IR EGCs density within the musculature. This alteration in myenteric EGCs density with age may contribute to colonic dysfunction.

Recognition of immune reactive proteins as a potential multiepitope vaccine candidate of Taenia solium cysticerci through proteomic approach.

Metacestode, the larva of Taenia solium, is the causative agent for neurocysticercosis (NCC), which causes epilepsy. The unavailability of a vaccine against human NCC is a major cause for its widespread prevalence across the globe. Therefore, the development of a reliable vaccine against NCC is the need of the hour. Employing a combination of proteomics and immunoinformatics, we endeavored to formulate a vaccine candidate. The immune reactive cyst fluid antigens of T. solium were identified by immune-blotting two-dimensional gels with NCC patient's sera, followed by Matrix-assisted laser desorption-ionization analysis. We performed a detailed proteomic study of these immune reactive proteins by utilizing immune-informatics tools, identified the nontoxic, nonallergic, B-cell epitopes, and collected epitopes with the least sequence homology with human and other Taenia species. These epitopes were joined through linkers to construct a multiepitope vaccine. Different physiochemical parameters such as molecular weight (23.82 kDa), instability (39.91), and aliphatic index (49.61) were calculated to ensure the stability of the linked peptides vaccine. The vaccine demonstrated stable interactions with different immune receptors like Toll-like receptor 4 and IgG confirming that it will effectively stimulate the host immune response. We anticipate that our designed B-cell linear epitope-based vaccine will show promising results in in vitro and in vivo assays. This study provides a platform that would be useful to develop other suitable vaccine candidates to prevent helminthic neglected tropical diseases in near future.

Human Taenia martis Neurocysticercosis, Switzerland.

Neurocysticercosis is almost exclusively caused by Taenia solium tapeworms. We describe a case of neurocysticercosis in Switzerland caused by infection with Taenia martis, the marten tapeworm, and review all 5 published cases of human infection with the marten tapeworm. In epidemiologically nonplausible cases of neurocysticercosis, zoonotic spillover infections should be suspected.

Triplex ELISA for Assessing Durability of Taenia solium Seropositivity after Neurocysticercosis Cure.

Neurocysticercosis prevalence estimates often are based on serosurveys. However, assessments of Taenia solium seropositivity durability in patients with various neurocysticercosis types are lacking. We optimized a triplex serologic ELISA by using synthetic GP50, T24H, and Ts18var3 antigens for T. solium. We used that assay to test sequential serologic responses over several years after neurocysticercosis cure in 46 patients, 9 each with parenchymal or ventricular neurocysticercosis and 28 with subarachnoid disease. Triplex results were concordant with 98% of positive and 100% of negative enzyme-linked immunoelectrotransfer blots. Eight years after neurocysticercosis cure, 11.1% of patients with parenchymal, 47.3% with subarachnoid, and 41.7% with ventricular disease were still seropositive. Median time to seroreversion after cure in this cohort in a T. solium nonendemic area was 2 years for parenchymal disease, 4 years for ventricular disease, and 8 years for subarachnoid disease. Our findings can inform epidemiologic models that rely on serosurveys to estimate disease burden.

Multiantigen print immunoassay (MAPIA) for the diagnosis of neurocysticercosis: a single-center diagnostic optimization and accuracy study in Lima, Peru.

Neurocysticercosis (NCC) is the most common helminthic infection of the human central nervous system. The antibody detection assay of choice is the enzyme-linked immunoelectrotransfer blot assay using lentil-lectin purified parasite antigens (LLGP-EITB, Western blot), an immunoassay with exceptional performance in clinical samples. However, its use is mainly restricted to a few research laboratories because the assay is labor-intensive and requires sophisticated equipment, expertise, and large amounts of parasite material for preparation of reagents. We report a new immunoprint assay (MAPIA) that overcomes most of these barriers. We initially compared the performance of five different antigen combinations in a subset of defined samples in the MAPIA format. After selecting the best-performing assay format (a combination of rGP50 + rT24H + sTs14 antigens), 148 archived serum samples were tested, including 40 from individuals with parenchymal NCC, 40 with subarachnoid NCC, and 68 healthy controls with no evidence of neurologic disease. MAPIA using three antigens (rGP50 + rT24H + sTs14) was highly sensitive and specific for detecting antibodies in NCC. It detected 39 out of 40 (97.5%) parenchymal NCC cases and 40/40 (100%) subarachnoid cases and was negative in 67 out of 68 (98.53%) negative samples. MAPIA using three recombinant and synthetic antigens is a simple and economical tool with a performance equivalent to the LLGP-EITB assay for the detection of specific antibodies to NCC. The MAPIA overcomes existing barriers to adoption of the EITG LLGP and is a candidate for worldwide use.

Development and Laboratory Evaluation of a Simple, Field-Applicable Coproantigen Enzyme-Linked Immunosorbent Assay for Diagnosis of Taeniasis in Northern Peru.

Coproantigen detection by enzyme-linked immunosorbent assay (coAg ELISA) is a vital tool for detecting and treating cases of Taenia solium taeniasis. However, the assay's procedures require costly materials and sophisticated equipment, which are typically inaccessible in rural settings where the disease is endemic. To overcome these barriers, we developed and evaluated a field-applicable coAg ELISA. The field coAg ELISA was developed and evaluated across four phases using known positive and negative stool samples collected from northern Peru. Phase I focused on field assay development, phase II on a small-scale performance evaluation, phase III on a large-scale evaluation, and phase IV on the use and reliability of a colorimetric scale card. All samples were processed using the field and standard assay procedures and compared using signal-to-noise ratios, correlation tests, performance characteristics, and agreement statistics where appropriate. The field coAg ELISA using reagents stored at -20°C and commercially available water and milk powder, and relying on spontaneous separation of the supernatant, had performance comparable to the standard assay. The field coAg ELISA was strongly correlated with the standard in both the small- and large-scale laboratory evaluation (r = 0.99 and r = 0.98, respectively). Finally, the field assay had an almost perfect agreement between independent readers (kappa = 0.975) and between each reader and the spectrophotometer. The field coAg ELISA demonstrated performance comparable to the standard, providing a low-cost alternative to the standard assay for identifying cases of intestinal taeniasis in a low-resource setting.

Risk mapping for Taenia solium: Applying multicriteria decision analysis in Lao PDR.

OBJECTIVES: Taenia solium is ranked the most significant global foodborne parasite and the leading cause of epilepsy in low and middle-income countries. Diagnostic challenges have hampered disease control efforts to date and WHO has called for the development of risk mapping tools to assist endemic countries. This study describes the application of multicriteria decision analysis to map the risk of T. solium in Lao PDR and acts as a case study for other endemic countries. METHODS: Multicriteria decision analysis was completed using census data on relevant risk factors in Lao PDR. Factors were weighted using an analytical hierarchy process. Village risk scores were calculated using a weighted linear combination and categorised using the Fisher-Jenks algorithm into low, medium, and high risk. District risk scores and categories were calculated using the mean village risk score for a district. Sensitivity analysis was completed by doubling and halving risk factor weights, one at a time, and assessing the standard deviation of scores and categories across all scenarios. RESULTS: A total of 2017 (23.7%) villages were classified as high risk, with 3312 (39.0%) medium and 3170 (37.3%) low risk. This resulted in 21 (14.2%) high-risk districts, 83 (56.1%) medium and 44 (29.7%) low-risk districts. The risk maps highlight two areas of interest which are high risk and low variation. The first is the northern province of Phongsaly, which is consistent with literature and anecdotal reports. The second is the southern Salavan and Xekong provinces, which have yet to be investigated in detail. CONCLUSIONS: Multicriteria decision analysis has provided a simple, rapid, and flexible approach to mapping the risk of T. solium in Lao PDR. The nature of the method means that it can be completed in any endemic country with available and appropriate risk factor data.

The challenges of detecting Taenia solium and neurocysticercosis in low and middle-income countries: A scoping review of Lao People's Democratic Republic.

OBJECTIVE: Taenia solium is a tapeworm of global importance due to the burden of disease associated with human epilepsy caused by neurocysticercosis. Unfortunately, diagnostic challenges impede control efforts in many low and middle-income countries. This review examines publications concerning Taenia species in the Lao PDR with a focus on T. solium to inform future research and control programmes. METHODS: PubMed and Scopus databases were primary sources of evidence. Publications must have reported taeniasis or T. solium results from Lao PDR. Publications repeating results or samples were combined into unique projects. RESULTS: A total of 64 publications were included and summarised into 46 projects. The majority of projects applied faecal microscopy as their only diagnostic technique. As a result, the specific species of Taenia was often not determined. Only five projects used molecular techniques to identify the species observed. Only case report of neurocysticercosis has been published. The northern region was included in half the number of projects compared to the south, despite being a high-risk area T. solium. CONCLUSIONS: The diagnostic challenge of determining the species of Taenia present in a faecal sample presents a significant limitation to the control of T. solium in Lao PDR and is an experience that is relevant to many other low and middle-income countries. There must be an improved understanding of the distribution and frequency of T. solium if disease control efforts are to be intensified to reduce the burden of neurocysticercosis, as encouraged by WHO and others. It is hoped that this can be achieved through non-biological risk mapping tools and the more frequent application of molecular tools to routine sample collection. Diagnostic tools that are applicable to low resource settings should be a priority area of research for T. solium.

Cerebral Taenia crassiceps larvae infection in a 71-year-old immunocompetent male.

We report a rare case of a cerebral infection with Taenia crassiceps tapeworm larvae in an immunocompetent 71-year-old German male. Initially, an intracerebral malignoma was suspected after the patient experienced stroke-like symptoms. After surgery, helminth larvae, later identified as T. crassiceps, were detected. Identification on the species level was possible by specific PCR and sequencing. After complete surgical removal, the patient was treated with albendazole and dexamethasone for two weeks. No residual symptoms were reported up to date.