Unusual neurological presentation of second stage African trypanosomiasis in a young boy: a case report.

BACKGROUND: In South Sudan, sleeping sickness is a frequent condition caused by human African trypanosomiasis. There are two stages that are well-known. When the CNS is affected, especially with Trypanosoma gambiense infection, the early hemolymphatic stage and the late encephalitic stage have been observed, including mental, motor, and sensory symptoms. In this case, second-stage African trypanosomiasis manifested itself in an atypical neurological manner. CASE PRESENTATION: A 16-year-old boy from South Sudan referred to Sudan National Centre for Neurological Sciences, Khartoum, Sudan suffering from non-convulsive status epilepticus, mental deterioration and behavioral changes for the last nine months. He was conscious but disorientated. Low hemoglobin concentration, elevated ESR, enlarged spleen and positive card agglutination test for trypanosomiasis was found in this patient. Electro-encephalogram (EEG) found an on-going generalized seizure activity. The patient showed improvement after management with carbamazepine and tonic. CONCLUSION: Our case highlights that late second stage African trypanosomiasis with neurological complications such as non-convulsive status epilepticus should be suspected in any patient who developed progressive cognitive decline and behavioral changes following long standing history of African Trypanosomiasis and routine Electro-encephalogram EEG is the best tool to diagnose non convulsive status epilepticus.

Mental distress and health-related quality of life in gambiense human African trypanosomiasis: a case-control study in the Democratic Republic of Congo.

BACKGROUND: The extent to which neuropsychiatric sequelae affects the mental health status and quality of life of former gambiense human African trypanosomiasis (gHAT) patients is not known. METHODS: We assessed anxiety, depression and health-related quality of life (HRQoL) in 93 patients and their age- and sex-matched controls using the Hospital Anxiety and Depression Scale, Becks Depression Inventory and the 36-item Short Form Health Survey in structured interviews in the Vanga health zone in the Democratic Republic of Congo. Data were analysed using Stata version 14.0. The degree of association between neurologic sequelae and mental distress was evaluated using the Student's t-test and χ2 or Fisher's exact tests, where appropriate, with a p-value <0.05 deemed to be statistically significant. RESULTS: We found that neurological sequelae persisted in former patients at least 15 y after treatment. Depression (p<0.001) and anxiety (p=0.001) were significantly higher in former patients with neurologic sequelae. The mean quality-of-life (QoL) scores were significantly lower for patients than in controls in the physical, emotional and mental health domains. CONCLUSIONS: The presence of neurological sequelae leads to mental distress and a diminished QoL in former gHAT patients. Minimising neurologic sequelae and incorporating psychosocial interventions should be essential management goals for gHAT.

Upregulation of sialyltransferases ST3Gal1 and ST6Gal1 promotes stabilization of erythrocyte mass and recovery of anemia in Trypanosoma brucei brucei-infected pigs.

The role of Sialyltransferases (STs) specifically subfamilies ST3Gal1 and ST6Gal1 tissue expression was investigated in the liver and kidney of Trypanosoma brucei brucei-infected and uninfected control pigs. The study was aimed to provide emerging target for treatment. Pigs were experimentally infected with 2 × 106 T. b. brucei (Federe strain); parasitemia was monitored by microscopy and tissue expression levels of ST3Gall and ST6Gall in the liver and kidney were assessed using quantitative real-time polymerase chain reaction (qRT-PCR). Parasitemia were undulating and anemia occurred significantly (P < 0.01) on day 13 in the infected pigs with an attempt to recover toward the termination of the study on day 21. The gene expressions for hepatic and renal ST3Gal1 and ST6Gal1 were significantly (P < 0.0001) upregulated 5-42 folds in the infected pig compared to the non-infected control group. It was concluded from the findings in this study that increased tissue expression of ST3Gal1 and ST6Gal1 in T b. brucei-infected pigs may play a pivotal role in the resialylation of desialylated red blood cells, thereby promoting recovery of the red blood cells and stabilization of erythrocyte mass in trypanosome-infected pigs. It is recommended that the expression of serum ST3Gal1 and ST6Gal1 be investigated further, in trypano-susceptible against trypano-tolerant breeds of animals to determine the role of these genes in trypano-tolerance.

Phloroglucinol as a Potential Candidate against Trypanosoma congolense Infection: Insights from In Vivo, In Vitro, Molecular Docking and Molecular Dynamic Simulation Analyses.

Sub-Saharan Africa is profoundly challenged with African Animal Trypanosomiasis and the available trypanocides are faced with drawbacks, necessitating the search for novel agents. Herein, the chemotherapeutic potential of phloroglucinol on T. congolense infection and its inhibitory effects on the partially purified T. congolense sialidase and phospholipase A2 (PLA2) were investigated. Treatment with phloroglucinol for 14 days significantly (p < 0.05) suppressed T. congolense proliferation, increased animal survival and ameliorated anemia induced by the parasite. Using biochemical and histopathological analyses, phloroglucinol was found to prevent renal damages and splenomegaly, besides its protection against T. congolense-associated increase in free serum sialic acids in infected animals. Moreover, the compound inhibited bloodstream T. congolense sialidase via mixed inhibition pattern with inhibition binding constant (Ki) of 0.181 µM, but a very low uncompetitive inhibitory effects against PLA2 (Ki > 9000 µM) was recorded. Molecular docking studies revealed binding energies of -4.9 and -5.3 kcal/mol between phloroglucinol with modeled sialidase and PLA2 respectively, while a 50 ns molecular dynamics simulation using GROMACS revealed the sialidase-phloroglucinol complex to be more compact and stable with higher free binding energy (-67.84 ± 0.50 kJ/mol) than PLA2-phloroglucinol complex (-77.17 ± 0.52 kJ/mol), based on MM-PBSA analysis. The sialidase-phloroglucinol complex had a single hydrogen bond interaction with Ser453 while none was observed for the PLA2-phloroglucinol complex. In conclusion, phloroglucinol showed moderate trypanostatic activity with great potential in ameliorating some of the parasite-induced pathologies and its anti-anemic effects might be linked to inhibition of sialidase rather than PLA2.

Autoimmunity to phosphatidylserine and anemia in African Trypanosome infections.

Anemia caused by trypanosome infection is poorly understood. Autoimmunity during Trypanosoma brucei infection was proposed to have a role during anemia, but the mechanisms involved during this pathology have not been elucidated. In mouse models and human patients infected with malaria parasites, atypical B-cells promote anemia through the secretion of autoimmune anti-phosphatidylserine (anti-PS) antibodies that bind to uninfected erythrocytes and facilitate their clearance. Using mouse models of two trypanosome infections, Trypanosoma brucei and Trypanosoma cruzi, we assessed levels of autoantibodies and anemia. Our results indicate that acute T. brucei infection, but not T. cruzi, leads to early increased levels of plasma autoantibodies against different auto antigens tested (PS, DNA and erythrocyte lysate) and expansion of atypical B cells (ABCs) that secrete these autoantibodies. In vitro studies confirmed that a lysate of T. brucei, but not T. cruzi, could directly promote the expansion of these ABCs. PS exposure on erythrocyte plasma membrane seems to be an important contributor to anemia by delaying erythrocyte recovery since treatment with an agent that prevents binding to it (Annexin V) ameliorated anemia in T. brucei-infected mice. Analysis of the plasma of patients with human African trypanosomiasis (HAT) revealed high levels of anti-PS antibodies that correlated with anemia. Altogether these results suggest a relation between autoimmunity against PS and anemia in both mice and patients infected with T. brucei.

Long-term sequelae of congenital gambiense human African trypanosomiasis.

BACKGROUND: The clinical presentation of gambiense human African trypanosomias (gHAT) is generally considered to be the same among children and adults. In general, when describing the clinical presentation of children with gHAT, no differentiation is made between congenital gHAT and gHAT acquired later. There is a lack of knowledge regarding the signs and symptoms attributable to congenital gHAT and its long-term sequelae. METHODS: Following an evaluation of the hospital register for gHAT, the authors observed that six children born to mothers with gHAT during their pregnancies still had sequelae of the infection. The six mothers were interviewed about their respective pregnancies and the developmental history of the children borne to the infected mothers. Furthermore, the children then underwent a complete physical examination with a focus on neuropsychiatric signs and symptoms. RESULTS: Five of the six patients are still seriously disabled. Behavioral changes are present in four patients, tremor, speech impairment, involuntary movements and pathologic the Barrés test and Mingazzini test in three patients and convulsions, pyramidal signs and decreased muscle tonus in two patients. Two patients cannot work and one has a sphincter disorder. CONCLUSIONS: Our study suggests that congenital gHAT may lead to long-lasting sequelae in babies born to mothers treated after delivery. The risk of embryo toxicity of treatment of mothers with gHAT must be balanced against the risk of congenital gHAT with long-term sequelae.

A Critical Blimp-1-Dependent IL-10 Regulatory Pathway in T Cells Protects From a Lethal Pro-inflammatory Cytokine Storm During Acute Experimental Trypanosoma brucei Infection.

In many infectious diseases, the immune response operates as a double-edged sword. While required for protective immunity, infection-induced inflammation can be detrimental if it is not properly controlled, causing collateral body damage and potentially leading to death. It is in this context that the potent anti-inflammatory cytokine interleukin-10 (IL-10) is required to dampen the pro-inflammatory immune response that hallmarks trypanosomosis. Effective control of this infection requires not just the action of antibodies specific for the parasite's variable surface glycoprotein (VSG) coat antigens, but also a pro-inflammatory immune response mediated mainly by IFNγ, TNF, and NO. However, strict control of inflammation is mandatory, as IL-10-deficient mice succumb from an unrestrained cytokine storm within 10 days of a Trypanosome brucei infection. The relevant cellular source of IL-10 and the associated molecular mechanisms implicated in its trypanosomosis associated production are poorly understood. Using an IL-10 reporter mouse strain (Vert-X), we demonstrate here that NK cells, CD8+ T cells and CD4+ T cells as well as B cells and plasma cells constitute potential cellular sources of IL-10 within the spleen and liver during acute infection. The IL-10 wave follows peak pro-inflammatory cytokine production, which accompanied the control of peak parasitemia. Similar results were observed following conventional experimental needle infection and physiological infections via T. brucei-infected tsetse flies. Our results show that conditional T cell-specific ablation of the IL-10 regulating Prdm1 gene (encoding for the Blimp-1 transcription factor), leads to an uncontrolled trypanosome-induced pro-inflammatory syndrome like the one observed in infected IL-10-deficient mice. This result indicates that the biological role of IL-10-derived from non-T cells, including NK cells, is of minor importance when considering host survival. The cytokine IL-27 that is also considered to be an IL-10 regulator, did not affect IL-10 production during infection. Together, these data suggest that T. brucei activates a Blimp-1-dependent IL-10 regulatory pathway in T cells that acts as a critical anti-inflammatory rheostat, mandatory for host survival during the acute phase of parasitemia.

All You Ever Wanted to Know About APOL1 and TLFs and Did Not Dare Ask.

Interest in trypanosome lytic factors (TLFs) and apolipoprotein L1, the ion channel-forming protein component of TLFs, has increased tenfold since 2010. This is due to the association of African variants of APOL1 with kidney disease such that interest has reached circles beyond parasitology. We have extensive experience purifying and working with these proteins and protein complexes. Herein we describe our detailed purification protocols to aid the new burgeoning field by providing an opportunity for consistency in reagents used across laboratories. We emphasize that it is imperative to maintain APOL1 protein intact (~42 kDa) to analyze the active ion channel-forming component/protein.

Trypanosoma brucei infection protects mice against malaria.

Sleeping sickness and malaria are parasitic diseases with overlapping geographical distributions in sub-Saharan Africa. We hypothesized that the immune response elicited by an infection with Trypanosoma brucei, the etiological agent of sleeping sickness, would inhibit a subsequent infection by Plasmodium, the malaria parasite, decreasing the severity of its associated pathology. To investigate this, we established a new co-infection model in which mice were initially infected with T. brucei, followed by administration of P. berghei sporozoites. We observed that a primary infection by T. brucei significantly attenuates a subsequent infection by the malaria parasite, protecting mice from experimental cerebral malaria and prolonging host survival. We further observed that an ongoing T. brucei infection leads to an accumulation of lymphocyte-derived IFN-γ in the liver, limiting the establishment of a subsequent hepatic infection by P. berghei sporozoites. Thus, we identified a novel host-mediated interaction between two parasitic infections, which may be epidemiologically relevant in regions of Trypanosoma/Plasmodium co-endemicity.

African trypanosomes expressing multiple VSGs are rapidly eliminated by the host immune system.

Trypanosoma brucei parasites successfully evade the host immune system by periodically switching the dense coat of variant surface glycoprotein (VSG) at the cell surface. Each parasite expresses VSGs in a monoallelic fashion that is tightly regulated. The consequences of exposing multiple VSGs during an infection, in terms of antibody response and disease severity, remain unknown. In this study, we overexpressed a high-mobility group box protein, TDP1, which was sufficient to open the chromatin of silent VSG expression sites, to disrupt VSG monoallelic expression, and to generate viable and healthy parasites with a mixed VSG coat. Mice infected with these parasites mounted a multi-VSG antibody response, which rapidly reduced parasitemia. Consequently, we observed prolonged survival in which nearly 90% of the mice survived a 30-d period of infection with undetectable parasitemia. Immunodeficient RAG2 knock-out mice were unable to control infection with TDP1-overexpressing parasites, showing that the adaptive immune response is critical to reducing disease severity. This study shows that simultaneous exposure of multiple VSGs is highly detrimental to the parasite, even at the very early stages of infection, suggesting that drugs that disrupt VSG monoallelic expression could be used to treat trypanosomiasis.

Association of APOL1 renal disease risk alleles with Trypanosoma brucei rhodesiense infection outcomes in the northern part of Malawi.

Trypanosoma brucei (T.b.) rhodesiense is the cause of the acute form of human African trypanosomiasis (HAT) in eastern and southern African countries. There is some evidence that there is diversity in the disease progression of T.b. rhodesiense in different countries. HAT in Malawi is associated with a chronic haemo-lymphatic stage infection compared to other countries, such as Uganda, where the disease is acute with more marked neurological impairment. This has raised the question of the role of host genetic factors in infection outcomes. A candidate gene association study was conducted in the northern region of Malawi. This was a case-control study involving 202 subjects, 70 cases and 132 controls. All individuals were from one area; born in the area and had been exposed to the risk of infection since birth. Ninety-six markers were genotyped from 17 genes: IL10, IL8, IL4, HLA-G, TNFA, IL6, IFNG, MIF, APOL, HLA-A, IL1B, IL4R, IL12B, IL12R, HP, HPR, and CFH. There was a strong significant association with APOL1 G2 allele (p = 0.0000105, OR = 0.14, CI95 = [0.05-0.41], BONF = 0.00068) indicating that carriers of the G2 allele were protected against T.b. rhodesiense HAT. SNP rs2069845 in IL6 had raw p < 0.05, but did not remain significant after Bonferroni correction. There were no associations found with the other 15 candidate genes. Our finding confirms results from other studies that the G2 variant of APOL1 is associated with protection against T.b. rhodesiense HAT.

Cardiac involvement in trypanosomiasis in sheep experimentally infected by Trypanosoma vivax (Ziemman, 1905).

The objective of the present study was to evaluate the clinical signs, electrocardiographic signs and evolution of histopathological lesions in the heart of sheep experimentally infected by Trypanosoma vivax during the acute and chronic phases of infection as well as to investigate the presence of parasitic DNA in the heart using polymerase chain reaction (PCR). Twenty-two male sheep were divided into the following four groups: G1, which consisted of six sheep infected by T. vivax that were evaluated until 20 days post-infection (dpi; acute phase); G2, which consisted of six sheep infected by T. vivax that were evaluated until 90 dpi (chronic phase); and G3 and G4 groups, which each consisted of five uninfected sheep. At the end of the experimental period, electrocardiographic evaluations and necroscopic examinations were performed. Fragments of the heart were collected and stained by Hematoxylin-Eosin and Masson's trichrome, and the fragments were also evaluated by PCR for T. vivax. G2 animals presented clinical signs suggestive of heart failure and electrocardiogram alterations characterized by prolonged P, T and QRS complex durations as well as by a cardiac electrical axis shift to the left and increased heart rate. In these animals, mononuclear multifocal myocarditis and interstitial fibrosis were also observed. PCR revealed positivity for T. vivax in two G1 animals and in all G2 animals. Thus, these findings suggested that T. vivax is responsible for the occurrence of cardiac lesions, which are related to heart failure, electrocardiographic alterations and mortality of the infected animals.

Coxiella burnetii associated with BVDV (Bovine Viral Diarrhea Virus), BoHV (Bovine Herpesvirus), Leptospira spp., Neospora caninum, Toxoplasma gondii and Trypanosoma vivax in reproductive disorders in cattle.

This is a cross-sectional study to assess the presence of antibodies in ruminants against selected pathogens associated with reproductive disorders in cattle in four Brazilian states, including the zoonotic agent Coxiella burnetii. The used tests were Virus Neutralization Assay for IBR and BVD, Microscopic Agglutination Test for Leptospira spp., Indirect Fluorescent Antibody Test (IFAT) for C. burnetii and Toxoplasma gondii, and Enzyme-Linked Immunosorbent Assay for Neospora caninum and Trypanosoma vivax. Seropositivity for C. burnetii was 13.7% with titers from 128 to 131,072; 57.8% for BoHV-1, with titers between 2 and 1,024; 47.1% for BVDV-1a, with titers from 10 to 5,120; 89.2% for N. caninum; 50% for T. vivax; and 52.0% for Leptospira spp., with titers between 100 to 800 (the following serovars were found: Tarassovi, Grippotyphosa, Canicola, Copenhageni, Wolffi, Hardjo, Pomona and Icterohaemorrhagiae); 19.6% for T. gondii with titer of 40. This is the first study that has identified C. burnetii in cattle associated with BoHV and BVDV, N. caninum, Leptospira spp., T. gondii and T. vivax. Thus, future studies should be conducted to investigate how widespread this pathogen is in Brazilian cattle herds.

Case Report: Trypanosoma brucei Gambiense Human African Trypanosomiasis as the Cause of Fever in an Inpatient with Multiple Myeloma and HIV-1 Coinfection.

We report the case of a 64-year-old woman found to have urban-acquired Trypanosoma brucei (T.b.) gambiense human African trypanosomiasis (HAT) as the cause of sustained fever starting 9 months after returning to Canada from Democratic Republic of the Congo, in the context of concomitant multiple myeloma and HIV-1 coinfection. Approaches for the management of both clinical stages of T.b. gambiense HAT are well defined for endemic settings using current diagnostics and treatments. However, few data inform the diagnosis and management of patients with bone marrow suppression from active malignancy, recent anticancer therapy, or HIV coinfection. We discuss the implications of immunosuppression for diagnosis and management of T.b. gambiense HAT.

Trypanostatic activity of geranylacetone: Mitigation of Trypanosoma congolense-associated pathological pertubations and insight into the mechanism of anaemia amelioration using in vitro and in silico models.

Trypanosoma congolense is an important pathogen that wreaks havoc in the livestock industry of the African continent. This study evaluated the in vivo antitrypanosomal activity of geranylacetone and its ameliorative effect on the disease-induced anaemia and organ damages as well as its inhibitory effects against trypanosomal sialidase using in vitro and in silico techniques. Geranylacetone was used to treat T. congolense infected rats, at a dose of 50 and 100 mg/kg BW, for 14 days where it was found to reduce the parasite burden in the infected animals. Moreover, 100 mg/kg BW of geranylacetone significantly (p < 0.05) ameliorated the anaemia, hepatic and renal damages caused by the parasite. This is in addition to the alleviation of the parasite-induced hepatosplenomegaly and upsurge in free serum sialic acid levels in the infected animals which were associated with the observed anaemia amelioration by the compound. Consequently, bloodstream T. congolense sialidase was partially purified on DEAE cellulose column and inhibition kinetic studies revealed that the enzyme was inhibited by geranylacetone via an uncompetitive inhibition pattern. In silico analysis using molecular docking with Autodock Vina indicated that geranylacetone binds to trypanosomal sialidase with a minimum free binding energy of -5.8 kcal/mol which was mediated by 26 different kinds of non-covalent interactions excluding hydrogen bond whilst Asp163 and Phe421 had the highest number of the interactions. The data suggests that geranylacetone has trypanostatic activity and could protect animals against the T. congolense-induced anaemia through the inhibition of sialidase and/or the protection of the parasite-induced hepatosplenomegaly.

Coxiella burnetii associated with BVDV (Bovine Viral Diarrhea Virus), BoHV (Bovine Herpesvirus), Leptospira spp, Neospora caninum, Toxoplasma gondii and Trypanosoma vivax in reproductive disorders in cattle / Coxiella burnetii associada ao BVDV (Vírus da Diarreia Viral Bovina), BoHV (Vírus do Herpes Bovino), Leptospira spp, Neospora caninum, Toxoplasma gondii e Trypanosoma vivax em distúrbios reprodutivos em bovinos

Abstract This is a cross-sectional study to assess the presence of antibodies in ruminants against selected pathogens associated with reproductive disorders in cattle in four Brazilian states, including the zoonotic agent Coxiella burnetii. The used tests were Virus Neutralization Assay for IBR and BVD, Microscopic Agglutination Test for Leptospira spp., Indirect Fluorescent Antibody Test (IFAT) for C. burnetii and Toxoplasma gondii, and Enzyme-Linked Immunosorbent Assay for Neospora caninum and Trypanosoma vivax. Seropositivity for C. burnetii was 13.7% with titers from 128 to 131,072; 57.8% for BoHV-1, with titers between 2 and 1,024; 47.1% for BVDV-1a, with titers from 10 to 5,120; 89.2% for N. caninum; 50% for T. vivax; and 52.0% for Leptospira spp., with titers between 100 to 800 (the following serovars were found: Tarassovi, Grippotyphosa, Canicola, Copenhageni, Wolffi, Hardjo, Pomona and Icterohaemorrhagiae); 19.6% for T. gondii with titer of 40. This is the first study that has identified C. burnetii in cattle associated with BoHV and BVDV, N. caninum, Leptospira spp., T. gondii and T. vivax. Thus, future studies should be conducted to investigate how widespread this pathogen is in Brazilian cattle herds.

Resumo Este é um estudo transversal para avaliar a presença de anticorpos em ruminantes contra patógenos selecionados e associados a distúrbios reprodutivos em bovinos de quatro estados brasileiros, incluindo o agente zoonótico Coxiella burnetii. Os testes utilizados foram Teste de Vírus-Neutralização para BoHV e BVDV, teste de Aglutinação Microscópica para Leptospira spp., Reação de Imunofluorescência Indireta for C. burnetii e Toxoplasma gondii, e Ensaio de Imunoabsorção Enzimática para Neospora caninum e Trypanosoma vivax. A soropositividade para C. burnetii foi de 13,7% com títulos de 128 a 131.072; 57,8% para BoHV-1, com títulos entre 2 a 1.024; 47,1% para BVDV-1a, com títulos de 10 a 5.120; 89,2% para N. caninum; 50% para T. vivax; e 52,0% para Leptospira spp., com títulos entre 100 a 800 (sorovares encontrados: Tarassovi, Grippotyphosa, Canicola, Copenhageni, Wolffi, Hardjo, Pomona e Icterohaemorrhagiae) 19,6% para T. gondii com título de 40. Este é o primeiro estudo que evidencia a participação de C. burnetii em bovinos associada ao Vírus da Rinotraqueíte bovina infecciosa e da diarreia viral bovina, N. caninum, Leptospira spp., T. gondii e T. vivax em bovinos. Desta forma, futuros estudos devem ser conduzidos a fim de investigar o quão disseminado se encontra este patógeno em rebanhos bovinos brasileiros.

Sleeping sickness is a circadian disorder.

Sleeping sickness is a fatal disease caused by Trypanosoma brucei, a unicellular parasite that lives in the bloodstream and interstitial spaces of peripheral tissues and the brain. Patients have altered sleep/wake cycles, body temperature, and endocrine profiles, but the underlying causes are unknown. Here, we show that the robust circadian rhythms of mice become phase advanced upon infection, with abnormal activity occurring during the rest phase. This advanced phase is caused by shortening of the circadian period both at the behavioral level as well as at the tissue and cell level. Period shortening is T. brucei specific and independent of the host immune response, as co-culturing parasites with explants or fibroblasts also shortens the clock period, whereas malaria infection does not. We propose that T. brucei causes an advanced circadian rhythm disorder, previously associated only with mutations in clock genes, which leads to changes in the timing of sleep.

Clinical Spectrum, Etiology, and Outcome of Neurological Disorders in the Rural Hospital of Mosango, the Democratic Republic of Congo.

There is little published information on the epidemiology of neurological disorders in rural Central Africa, although the burden is considered to be substantial. This study aimed to investigate the pattern, etiology, and outcome of neurological disorders in children > 5 years and adults admitted to the rural hospital of Mosango, province of Kwilu, Democratic Republic of Congo, with a focus on severe and treatable infections of the central nervous system (CNS). From September 2012 to January 2015, 351 consecutive patients hospitalized for recent and/or ongoing neurological disorder were prospectively evaluated by a neurologist, subjected to a set of reference diagnostic tests in blood or cerebrospinal fluid, and followed-up for 3-6 months after discharge. No neuroimaging was available. Severe headache (199, 56.7%), gait/walking disorders (97, 27.6%), epileptic seizure (87, 24.8%), and focal neurological deficit (86, 24.5%) were the predominant presentations, often in combination. Infections of the CNS were documented in 63 (17.9%) patients and mainly included bacterial meningitis and unspecified meningoencephalitis (33, 9.4%), second-stage human African trypanosomiasis (10, 2.8%), and human immunodeficiency virus (HIV)-related neurological disorders (10, 2.8%). Other focal/systemic infections with neurological manifestations were diagnosed in an additional 60 (17.1%) cases. The leading noncommunicable conditions were epilepsy (61, 17.3%), psychiatric disorders (56, 16.0%), and cerebrovascular accident (23, 6.6%). Overall fatality rate was 8.2% (29/351), but up to 23.8% for CNS infections. Sequelae were observed in 76 (21.6%) patients. Clinical presentations and etiologies of neurological disorders were very diverse in this rural Central African setting and caused considerable mortality and morbidity.

AcSDKP is down-regulated in anaemia induced by Trypanosoma brucei infection in mice.

Background: Anaemia commonly results from destruction of erythrocytes in the peripheral blood and failure of the bone marrow haematopoietic cells to replenish the erythrocytes. The mechanisms involved in trypanosoma-induced anaemia, including the role of the bone marrow haematopoietic cells are incompletely understood. We studied the responses of a tetrapeptide, AcSDKP, and IL-10, and their association with bone marrow nucleated cells in a Trypanosoma brucei brucei GVR35 experimental infection model. Methods: Mouse infection was done intraperitoneally with 1 × 103 trypanosomes/mL. Mice were either infected or left uninfected (N = 100). At days 0, 9, 16, 23, 30, 37, and 44 post-infection, mice were euthanised and blood was collected by cardiac puncture to examine for parasitaemia and packed cell volume (PCV) and then centrifuged for plasma, which was used for cytokine ELISA. The mice's femurs were also dissected and bone marrow was collected for femur cellularity. Results: PCV dropped from 39.6% to 27% in infected animals by day 9 and remained low (relative to uninfected mice) for the duration of the experiment. AcSDKP levels decreased from day 0 (11.5 × 104 pg/mL) to day 16 (10 × 104), and increased by day 30 (12.6 × 104). There was a significant difference at day 16 (P = 0.023) between the infected and uninfected groups. By contrast, expression of IL-10 markedly increased between day 0 (18.6 pg/mL) and day 16 (145 pg/mL) and decreased by day 30 (42.8 pg/mL). There was also a significant difference in IL-10 expression between infected and uninfected mice at day 16 (P < 0.001). Bone marrow nucleated cells were significantly reduced during periods of low plasma AcSDKP and high plasma IL-10 concentrations (5.4 × 106 infected vs 6.2 × 106 on day 0 and 4.9 × 106 infected vs 10 × 106 uninfected on day 16). Conclusions: These data unravel a possible negative feedback interaction between AcSDKP and IL-10 in trypanosome infection. More importantly, this study implicates an IL-10/AcSDKP cytokine network in the regulation of bone marrow nucleated cells and provides a new potential mechanism in the pathogenesis of trypanosoma-induced anaemia. Further mechanistic blocking experiments on AcSDKP and IL-10 are recommended to further clarify understanding of the interaction.

Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes.

BACKGROUND: The timing of Trypanosoma brucei entry into the brain parenchyma to initiate the second, meningoencephalitic stage of human African trypanosomiasis or sleeping sickness is currently debated and even parasite invasion of the neuropil has been recently questioned. Furthermore, the relationship between neurological features and disease stage are unclear, despite the important diagnostic and therapeutic implications. METHODOLOGY: Using a rat model of chronic Trypanosoma brucei brucei infection we determined the timing of parasite and T-cell neuropil infiltration and its correlation with functional changes. Parasite DNA was detected using trypanosome-specific PCR. Body weight and sleep structure alterations represented by sleep-onset rapid eye movement (SOREM) periods, reported in human and experimental African trypanosomiasis, were monitored. The presence of parasites, as well as CD4+ and CD8+ T-cells in the neuropil was assessed over time in the brain of the same animals by immunocytochemistry and quantitative analyses. PRINCIPAL FINDINGS: Trypanosome DNA was present in the brain at day 6 post-infection and increased more than 15-fold by day 21. Parasites and T-cells were observed in the parenchyma from day 9 onwards. Parasites traversing blood vessel walls were observed in the hypothalamus and other brain regions. Body weight gain was reduced from day 7 onwards. SOREM episodes started in most cases early after infection, with an increase in number and duration after parasite neuroinvasion. CONCLUSION: These findings demonstrate invasion of the neuropil over time, after an initial interval, by parasites and lymphocytes crossing the blood-brain barrier, and show that neurological features can precede this event. The data thus challenge the current clinical and cerebrospinal fluid criteria of disease staging.