Comparison on simultaneous caillary and venous parasite density and genotyping results from children and adults with uncomplicated malaria: a prospective observational study in Uganda.

BACKGROUND: Blood smear microscopy remains the gold-standard method to diagnose and quantify malaria parasite density. In addition, parasite genotyping of select loci is the most utilized method for distinguishing recrudescent and new infections and to determine the number of strains per sample. In research settings, blood may be obtained from capillary or venous compartments, and results from these matrices have been used interchangeably. Our aim was to compare quantitative results for parasite density and strain complexity from both compartments. METHODS: In a prospective observational study, children and adults presenting with uncomplicated Plasmodium falciparum malaria, simultaneous capillary and venous blood smears and dried blood spots were collected over 42-days following treatment with artemether-lumefantrine. Blood smears were read by two microscopists, any discrepancies resolved by a third reader. Parasite DNA fingerprinting was conducted using six microsatellites. Bland Altman analysis and paired t-test/McNemar's test were used to assess the difference in density readings and measurements. RESULTS: Two hundred twenty-three participants were included in the analysis (177 children (35 HIV-infected/142 HIV-uninfected), 21 HIV-uninfected pregnant women, and 25 HIV-uninfected non-pregnant adults). Parasite density measurements did not statistically differ between capillary and venous blood smears at the time of presentation, nor over the course of 42-day follow-up. Characterization of merozoite surface protein-2 (MSP-2) genetic polymorphism demonstrated a higher level of strain diversity at the time of presentation in venous samples, as compared with capillary specimens (p = 0.02). There was a high degree of variability in genotype-corrected outcomes when pairs of samples from each compartment were compared using MSP-2 alone, although the variability was reduced with the use of multiple markers. CONCLUSIONS: Parasite density measurements do not statistically differ between capillary and venous compartments in all studied demographic groups at the time of presentation with malaria, or over the course of follow-up. More strains were detected by MSP-2 genotyping in venous samples than in capillary samples at the time of malaria diagnosis. The use of multiple polymorphic markers reduces the impact of variability in strain detection on genotype-corrected outcomes. This study confirms that both capillary and venous compartments can be used for sampling with confidence in the clinical research setting. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov under registration no. NCT01717885 .

Oral iron supplements for children in malaria-endemic areas.

BACKGROUND: Iron-deficiency anaemia is common during childhood. Iron administration has been claimed to increase the risk of malaria. OBJECTIVES: To evaluate the effects and safety of iron supplementation, with or without folic acid, in children living in areas with hyperendemic or holoendemic malaria transmission. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library, MEDLINE (up to August 2015) and LILACS (up to February 2015). We also checked the metaRegister of Controlled Trials (mRCT) and World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to February 2015. We contacted the primary investigators of all included trials, ongoing trials, and those awaiting assessment to ask for unpublished data and further trials. We scanned references of included trials, pertinent reviews, and previous meta-analyses for additional references. SELECTION CRITERIA: We included individually randomized controlled trials (RCTs) and cluster RCTs conducted in hyperendemic and holoendemic malaria regions or that reported on any malaria-related outcomes that included children younger than 18 years of age. We included trials that compared orally administered iron, iron with folic acid, and iron with antimalarial treatment versus placebo or no treatment. We included trials of iron supplementation or fortification interventions if they provided at least 80% of the Recommended Dietary Allowance (RDA) for prevention of anaemia by age. Antihelminthics could be administered to either group, and micronutrients had to be administered equally to both groups. DATA COLLECTION AND ANALYSIS: The primary outcomes were clinical malaria, severe malaria, and death from any cause. We assessed the risk of bias in included trials with domain-based evaluation and assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We performed a fixed-effect meta-analysis for all outcomes and random-effects meta-analysis for hematological outcomes, and adjusted analyses for cluster RCTs. We based the subgroup analyses for anaemia at baseline, age, and malaria prevention or management services on trial-level data. MAIN RESULTS: Thirty-five trials (31,955 children) met the inclusion criteria. Overall, iron does not cause an excess of clinical malaria (risk ratio (RR) 0.93, 95% confidence intervals (CI) 0.87 to 1.00; 14 trials, 7168 children, high quality evidence). Iron probably does not cause an excess of clinical malaria in both populations where anaemia is common and those in which anaemia is uncommon. In areas where there are prevention and management services for malaria, iron (with or without folic acid) may reduce clinical malaria (RR 0.91, 95% CI 0.84 to 0.97; seven trials, 5586 participants, low quality evidence), while in areas where such services are unavailable, iron (with or without folic acid) may increase the incidence of malaria, although the lower CIs indicate no difference (RR 1.16, 95% CI 1.02 to 1.31; nine trials, 19,086 participants, low quality evidence). Iron supplementation does not cause an excess of severe malaria (RR 0.90, 95% CI 0.81 to 0.98; 6 trials, 3421 children, high quality evidence). We did not observe any differences for deaths (control event rate 1%, low quality evidence). Iron and antimalarial treatment reduced clinical malaria (RR 0.54, 95% CI 0.43 to 0.67; three trials, 728 children, high quality evidence). Overall, iron resulted in fewer anaemic children at follow up, and the end average change in haemoglobin from base line was higher with iron. AUTHORS' CONCLUSIONS: Iron treatment does not increase the risk of clinical malaria when regular malaria prevention or management services are provided. Where resources are limited, iron can be administered without screening for anaemia or for iron deficiency, as long as malaria prevention or management services are provided efficiently.

Severe falciparum malaria treated with artesunate complicated by delayed onset haemolysis and acute kidney injury.

BACKGROUND: Severe falciparum malaria may be complicated by haemolysis after parasite clearance, however the mechanisms remain unclear. Recent reports describe a pattern of delayed onset haemolysis among non-immune travellers with hyperparasitaemia treated with intravenous artesunate, termed post-artesunate delayed haemolysis (PADH). The occurrence and clinical impact of PADH following severe malaria infections in areas of unstable transmission are unknown. CASE: A 45-year-old Bangladeshi male was initially admitted to a local hospital with severe falciparum malaria complicated by hyperparasitaemia and treated with intravenous artesunate. Twenty days from his first presentation he was readmitted with delayed onset haemolytic anaemia and acute kidney injury. Multiple blood transfusions and haemodialysis were required. Renal biopsy revealed acute tubular injury and haem pigment nephropathy. His haemoglobin and renal function recovered to baseline after 62 days from his second admission. DISCUSSION: This case highlights the differential diagnosis of post-malaria delayed onset haemolysis, including the recently described syndrome of post-artemisinin delayed haemolysis. The pathophysiology contributing to acute kidney injury in this patient and the limited treatment options are discussed. CONCLUSIONS: This report describes PADH complicated by acute kidney injury in an adult patient living in a malaria hypoendemic region who subsequently required blood transfusions and haemodialysis. This case emphasizes the importance of routine follow up of haemoglobin and renal function in artesunate-treated patients who have recovered from severe malaria.

Profound autoimmune hemolysis and Evans syndrome in two asplenic patients with babesiosis.

BACKGROUND: Evans syndrome (ES) is characterized by the simultaneous or sequential presence of multiple autoimmune cytopenias. It is often secondary to rheumatologic disorders or lymphoid malignancies, but has not previously been associated with babesiosis. Here we present two cases of severe cytopenias in asplenic patients precipitated by active babesiosis. CASE REPORT: The first patient had a history of Hodgkin's lymphoma in remission and autoimmune hemolytic anemia (AIHA) treated by splenectomy 12 years prior who presented with severe AIHA and thrombocytopenia after Babesia infection. The second patient had a history of ES requiring splenectomy, which relapsed after Babesia infection. RESULTS: The complex presentation and medical histories of both patients made the diagnosis challenging. Both patients' cytopenias responded to therapy, although the use of immunosuppressive agents in patients with active hematologic infections was challenging and required a multidisciplinary approach. CONCLUSION: These two cases illustrate the possibility of babesiosis to not only reactivate ES in asplenic patients, but also precipitate increased levels of immune deregulation, potentially provoking ES, a phenomenon not previously reported.

Measurement of the uniaxial mechanical properties of rat brains infected by Plasmodium berghei ANKA.

Degenerative and demyelinating diseases are known to alter the mechanical properties of brain tissue. While few studies have characterized these biomechanical changes, it is clear that accurate characterization of the mechanical properties of diseased brain tissue could be a substantial asset to neuronavigation and surgery simulation through haptic devices. In this study, samples of brain tissue from rats infected with Plasmodium berghei ANKA, an African murine malaria parasite, are evaluated using a uniaxial tensile test machine. Infected brains having different levels of parasitemia are mounted on the testing machine and extended until failure of the tissue. The stress-strain curve of each sample is obtained and compared to healthy rat brain tissue. Young's modulus of each sample is extracted from the Hookean part of the stress-strain diagram. Young's modulus of rats' brain shows considerable difference among the samples having various levels of parasitemia compared with the controls. For instance, the brains with 0% (control), 1.5%, and 9% parasitemia showed a Young's modulus of 46.15, 54.54, and 266.67 kPa, respectively. This suggests sequestration of the stiffened and less deformable parasitized red blood cells in the brain microvasculature.

Early age at time of primary Epstein-Barr virus infection results in poorly controlled viral infection in infants from Western Kenya: clues to the etiology of endemic Burkitt lymphoma.

BACKGROUND: Infection with Epstein-Barr virus (EBV) early in life and repeated malaria exposure have been proposed as risk factors for endemic Burkitt lymphoma (eBL). METHODS: Infants were enrolled from 2 rural sites in Kenya: the Kisumu District, where malaria transmission is holoendemic and risk for eBL is high, and the Nandi District, where malaria transmission is limited and the risk for eBL is low. Blood samples were taken from infants through 2 years of age to measure EBV viral load, EBV antibodies, and malaria parasitemia. RESULTS: We observed a significantly younger age at time of primary EBV infection in children from Kisumu compared with children from Nandi (mean age, 7.28 months [±0.33 SEM] in Kisumu vs 8.39 months [±0.26 SEM] in Nandi), with 35.3% of children in Kisumu infected before 6 months of age. To analyze how different predictors affected EBV viral load over time, we performed multilevel mixed modeling. This modeling revealed that residence in Kisumu and younger age at first EBV infection were significant predictors for having a higher EBV viral load throughout the period of observation. CONCLUSIONS: Children from a region at high risk for eBL were infected very early in life with EBV, resulting in higher viral loads throughout infancy.

Oral iron supplements for children in malaria-endemic areas.

BACKGROUND: Iron-deficiency anaemia is common during childhood. Iron supplementation has been claimed to increase the risk of malaria. OBJECTIVES: To assess the effect of iron on malaria and deaths. SEARCH STRATEGY: We searched The Cochrane Library, PUBMED, MEDLINE, LILACS; and trial registry databases, all up to June 2011. We scanned references of included trials. SELECTION CRITERIA: Individually and cluster randomized controlled trials conducted in hypoendemic to holoendemic malaria regions and including children below 18 years of age. We included trials comparing orally administered iron, iron with antimalarial treatment, or iron with folic acid versus placebo or no treatment. Iron fortification was excluded. Antihelminthics could be administered to either group. Additional micronutrients had to be administered equally to both groups. DATA COLLECTION AND ANALYSIS: The primary outcomes were clinical (symptomatic) malaria, severe malaria, and death. Two authors independently selected the studies and extracted the data. We assessed heterogeneity and conducted subgroup analyses by the presence of anaemia at baseline, age, and malaria endemicity. We assessed risk of bias using domain-based evaluation. We performed a fixed-effect meta-analysis for all outcomes and random-effects meta-analysis for hematological outcomes. We adjusted analyses for cluster randomized trials. MAIN RESULTS: Seventy-one trials (45,353 children) were included. For clinical malaria, no significant difference between iron alone and placebo was detected, (risk ratio (RR) 0.99, 95% confidence intervals (CI) 0.90 to 1.09, 13 trials). The results were similar in the subgroups of non-anaemic children and children below 2 years of age. There was no significant difference in deaths in hyper- and holoendemic areas, risk difference +1.93 per 1000 children (95% CI -1.78 to 5.64, 13 trials, 17,898 children). Iron administered for treatment of anaemia resulted in a larger increase in haemoglobin than iron given for prevention, and the benefit was similar in hyper- or holoendemic and lower endemicity settings. Iron and folic acid supplementation resulted in mixed results for severe malaria. Overall, the risk for clinical malaria was higher with iron or with iron plus folic acid in trials where services did not provide for malaria surveillance and treatment. Iron with antimalarial treatment significantly reduced malaria. Iron supplementation during an acute attack of malaria did not increase the risk for parasitological failure, (RR 0.96, 95% CI 0.74 to 1.24, three trials) or deaths. AUTHORS' CONCLUSIONS: Iron alone or with antimalaria treatment does not increase the risk of clinical malaria or death when regular malaria surveillance and treatment services are provided. There is no need to screen for anaemia prior to iron supplementation.

Plasmodium falciparum infection significantly impairs placental cytokine profile in HIV infected Cameroonian women.

BACKGROUND: Placental cytokines play crucial roles in the establishment and maintenance of pregnancy as well as protecting the foetus from infections. Previous studies have suggested the implication of infections such as P. falciparum and HIV in the stimulation of placental cytokines. This study assessed the impact of P. falciparum on placental cytokine profiles between HIV-1 positive and negative women. MATERIALS AND METHODS: P. falciparum infection was checked in peripheral and placental blood of HIV-1 negative and positive women by the thick blood smear test. Cytokines proteins and messenger RNAs were quantified by ELISA and real time PCR, respectively. Non-parametric tests were used for statistical analyses. RESULTS: Placental and peripheral P. falciparum infections were not significantly associated with HIV-1 infection (OR: 1.4; 95% confidence interval (95%CI): 0.5-4.2; p = 0.50 and OR: 0.6; 95%CI: 0.3-1.4; p = 0.26, respectively). Conversely, placental P. falciparum parasitemia was significantly higher in the HIV-1 positive group (p = 0.04). We observed an increase of TNF-alpha mRNA median levels (p = 0.02) and a trend towards a decrease of IL-10 mRNA (p = 0.07) in placenta from HIV-1 positive women compared to the HIV negative ones leading to a median TNF-alpha/IL-10 mRNA ratio significantly higher among HIV-1 positive than among HIV-1 negative placenta (p = 0.004; 1.5 and 0.8, respectively). Significant decrease in median secreted cytokine levels were observed in placenta from HIV-1 positive women as compared to the HIV negative however these results are somewhat indicative since it appears that differences in cytokine levels (protein or mRNA) between HIV-1 positive and negative women depend greatly on P.falciparum infection. Within the HIV-1 positive group, TNF-alpha was the only cytokine significantly associated with clinical parameters linked with HIV-1 MTCT such as premature rupture of membranes, CD4 T-cell number, plasma viral load and delay of NVP intake before delivery. CONCLUSIONS: These results show that P. falciparum infection profoundly modifies the placenta cytokine environment and acts as a confounding factor, masking the impact of HIV-1 in co-infected women. This interplay between the two infections might have implications in the in utero MTCT of HIV-1 in areas where HIV-1 and P. falciparum co-circulate.

Oral iron supplementation for preventing or treating anaemia among children in malaria-endemic areas.

BACKGROUND: Iron-deficiency anaemia is common during childhood. Iron supplementation has been claimed to increase the risk of malaria. OBJECTIVES: To assess the effect of iron on malaria and deaths. SEARCH STRATEGY: We searched The Cochrane Library (2009, issue 1); MEDLINE; EMBASE; LILACS and metaRegister of Controlled Trials, all up to March 2009. We scanned references of included trials. SELECTION CRITERIA: Individually and cluster-randomized controlled trials conducted in hypoendemic to holoendemic malaria regions and including children < 18 years. We included trials comparing orally administered iron with or without folic acid vs. placebo or no treatment. Iron fortification was excluded. Antimalarials and/or antiparasitics could be administered to either group. Additional micronutrients could only be administered equally to both groups. DATA COLLECTION AND ANALYSIS: The primary outcomes were malaria-related events and deaths. Secondary outcomes included haemoglobin, anaemia, other infections, growth, hospitalizations, and clinic visits. We assessed risk of bias using domain-based evaluation. Two authors independently selected studies and extracted data. We contacted authors for missing data. We assessed heterogeneity. We performed fixed-effect meta-analysis and presented random-effects results when heterogeneity was present. We present pooled risk ratios (RR) with 95% confidence intervals (CIs). We used adjusted analyses for cluster-randomized trials. MAIN RESULTS: Sixty-eight trials (42,981 children) fulfilled the inclusion criteria. Iron supplementation did not increase the risk of clinical malaria (RR 1.00, 95% CI 0.88 to 1.13; 22,724 children, 14 trials, random-effects model). The risk was similar among children who were non-anaemic at baseline (RR 0.96, 95% CI 0.85 to 1.09). An increased risk of malaria with iron was observed in trials that did not provide malaria surveillance and treatment. The risk of malaria parasitaemia was higher with iron (RR 1.13, 95% CI 1.01 to 1.26), but there was no difference in adequately concealed trials. Iron + antimalarial was protective for malaria (four trials). Iron did not increase the risk of parasitological failure when given during malaria (three trials). There was no increased risk of death across all trials comparing iron versus placebo (RR 1.11, 95% CI 0.91 to 1.36; 21,272 children, 12 trials). Iron supplementation increased haemoglobin, with significant heterogeneity, and malaria endemicity did not affect this effect. Growth and other infections were mostly not affected by iron supplementation. AUTHORS' CONCLUSIONS: Iron does not increase the risk of clinical malaria or death, when regular malaria surveillance and treatment services are provided. There is no need to screen for anaemia prior to iron supplementation.

Malaria parasitemia associated with febrile neutropenia in African patients undergoing chemotherapy for haematological malignancies. A report of three patients.

BACKGROUND: Very little is documented in the medical literature on the association between malaria parasitemia and febrile neutropenia in patients undergoing cancer chemotherapy. METHODS: This report will concentrate on the clinical presentation and outcome of 3 patients with haematological malignancies undergoing chemotherapy who developed febrile neutropenia and malaria parasitemia concurrently. RESULTS: Three patients infected with documented malaria during a febrile neutropenic episode are presented. Two patients (1 with Hodgkin's disease and the other with non-Hodgkin's lymphoma) were successfully treated and are alive after a follow-up period of 120 and 90 months, respectively. A third patient with acute lymphoblastic leukaemia developed renal failure as a complicating factor of malaria and died. CONCLUSION: It is suggested that malaria should be considered as a possible cause or a complicating factor of febrile neutropenia in patients undergoing cancer chemotherapy in endemic malaria areas.

Folic acid treatment of Zambian children with moderate to severe malaria anemia.

Whether administration of folic acid to children with malaria anemia is helpful is controversial. Therefore, we conducted a randomised, placebo-controlled trial of 14 days of treatment with folic acid (1 mg/d) in Zambian children with malaria anemia treated with either sulfadoxine/pyrimethamine (SP) or atovaquone/proguanil (AP). Among children who received SP, the prevalence of parasitemia was higher in children treated with folic acid than among those given placebo at days 3, 7, and 14 after the start of treatment, and the difference at day 3 was statistically significant (P = 0.013). Folic acid treatment had no effect on parasitemia in children treated with AP. Administration of folic acid led to a small increase in packed cell volume over that seen in the placebo group at days 14 and 28 after the start of treatment.

Pathology of Tnf-deficient mice infected with Plasmodium chabaudi adami 408XZ.

Tumor necrosis factor alpha (Tnf) plays a pleiotropic role in murine malaria. Some investigations have correlated Tnf with hypothermia, hyperlactatemia, hypoglycemia, and a suppression of the erythropoietic response, although others have not. In this study, we have evaluated parasitemia, survival rate and several pathological features in C57BL/6JTnf(-/-) and C57BL/6JTnf(+/+) mice after infection with Plasmodium chabaudi adami 408XZ. Compared to the C57BL/6JTnf(+/+) mice, C57BL/6JTnf(-/-) mice showed increased parasitemia and decreased survival rate, whereas blood glucose, blood lactate and body weight were not significantly different. However, C57BL/6JTnf(-/-) mice suffered significantly more from severe anemia and hypothermia than C57BL/6JTnf(+/+) mice. These results suggest that Tnf is an important mediator of parasite control, but not of anemia development. We hypothesize that the high mortality observed in the Tnf knock-out mice is due to increased anemia and pathology as a direct result of increased levels of parasitemia.

Mice deficient in LRG-47 display enhanced susceptibility to Trypanosoma cruzi infection associated with defective hemopoiesis and intracellular control of parasite growth.

IFN-gamma is known to be required for host control of intracellular Trypanosoma cruzi infection in mice, although the basis of its protective function is poorly understood. LRG-47 is an IFN-inducible p47GTPase that has been shown to regulate host resistance to intracellular pathogens. To investigate the possible role of LRG-47 in IFN-gamma-dependent control of T. cruzi infection, LRG-47 knockout (KO) and wild-type (WT) mice were infected with the Y strain of this parasite, and host responses were analyzed. When assayed on day 12 after parasite inoculation, LRG-47 KO mice, in contrast to IFN-gamma KO mice, controlled early parasitemia almost as effectively as WT animals. However, the infected LRG-47 KO mice displayed a rebound in parasite growth on day 15, and all succumbed to the infection by day 19. Additional analysis indicated that LRG-47-deficient mice exhibit unimpaired proinflammatory responses throughout the infection. Instead, reactivated disease in the KO animals was associated with severe splenic and thymic atrophy, anemia, and thrombocytopenia not observed in their WT counterparts. In addition, in vitro studies revealed that IFN-gamma-stimulated LRG-47 KO macrophages display defective intracellular killing of amastigotes despite normal expression of TNF and NO synthetase type 2 and that both NO synthetase type 2 and LRG-47 are required for optimum IFN-gamma-dependent restriction of parasite growth. Together, these data establish that LRG-47 can influence pathogen control by simultaneously regulating macrophage-microbicidal activity and hemopoietic function.

Long-term follow-up of co-infected HIV and Trypanosoma cruzi Brazilian patients.

Three cases of Trypanosoma cruzi-HIV co-infected haemophiliacs are described. Parasitological (xenodiagnosis, haemoculture, PCR) and immunological (CD4+ and CD8+ T cell counts, in vitro lymphoproliferative responses) studies were performed. Hybridization of isolated parasites with a specific probe confirmed the T. cruzi aetiology. We observed that despite the high parasitaemia, no clinical or parasitological evidence of T. cruzi reactivation was detected. CD4+ T cells decreased with time in two patients and the lymphocyte proliferative response to T. cruzi was very low in all patients. These data suggest that T. cruzi infection may have a long silent course in immunosuppressed HIV patients. Therefore, this parasitic infection should be investigated in any AIDS patient coming from areas endemic for Chagas' disease.

Plasmodium falciparum causing hemophagocytic syndrome after allogeneic blood stem cell transplantation.

We describe a case of Plasmodium falciparum infection in a 25-year-old male patient with a myelodysplastic syndrome, who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) in September 2003. Conditioning regimen consisted of total body irradiation (10 Gy) and cyclophosphamide 60 mg/kg for 2 days. A dose of 4 x 10(6) CD34+ cells/kg was transfused. Engraftment was well documented on day 17 post-transplantation. Spiking fevers occurred on days 19 and 21, associated with a pancytopenia, hepatosplenomegaly and neurological signs. P. falciparum parasites were found on the peripheral blood smear (parasitemia = 23%). Marrow aspiration showed P. falciparum parasites and proliferation of mature histiocytes with hemophagocytosis. Quinine 10 mg/kg i.v. three times a day for 10 consecutive days was given. The fever subsided within 3 days, and pancytopenia vanished in 14 days. Parasitemia cleared in 6 days. The patient left the unit on day 46 with no further complications. The screening of donors showed that infection was acquired from two blood units (from a single donor) given 5 days before transplantation. We report the first case of profound hemophagocytosis in immunosuppressed patient with malaria of high parasitemia after a bone marrow transplant.

Visceral leishmaniasis and HIV co-infection: a rare case of pulmonary and oral localization.

Visceral leishmaniasis (VL) has increased as a complicating infection in subjects with human immunodeficiency virus (HIV) in countries bordering the Mediterranean sea. The clinical course as well as organ involvement of VL are often atypical in HIV positive subjects. In this study a case of VL with pulmonary and oral mucose localisation in a patient with acquired immune deficiency syndrome (AIDS), is reported. These findings, together with the presence of the parasite in the peripheral blood smear, confirm that in HIV positive patients the impaired immune system allows the spreading and the atypical localisation of the Leishmania amastigotes more easily than in immuno-competent individuals. In endemic areas and in HIV positive subjects a systemic and careful parasitological follow-up is necessary to ensure that any clinical form of leishmaniasis is not overlooked.

Neospora caninum-associated abortion in cattle: the time of experimentally-induced parasitaemia during gestation determines foetal survival.

The parasite, Neospora caninum is an important cause of abortion in cattle. It is transmitted vertically or horizontally and infection may result in abortion or the birth of a live, healthy but infected calf at full-term. Only a proportion of infected cattle abort and the pathogenesis of abortion is not understood. Groups of cattle were infected with 10(7) N. caninum tachyzoites intravenously at different times relative to gestation. Intravenous inoculation was chosen to reproduce the putative haematogenous spread of N. caninum following either recrudescence of endogenous infection or de novo infection. In all cattle, infection was accompanied by high gamma-interferon and lymphoproliferative responses, and a biased IgG2 response indicating that N. caninum infection is accompanied by a profound Th1 helper T cell-like response. Infection at 10 weeks gestation resulted in foetopathy and resorption of foetal tissues 3 weeks after infection in 5 out of 6 cows. Infection at 30 weeks gestation resulted in the birth of asymptomatic, congenitally-infected calves at full term in all 6 cows, whereas the 6 cows infected before artificial insemination gave birth to live, uninfected calves. These results suggest that the reason some cows abort is related to the time during gestation when they become infected or an existing infection recrudesces.

Delayed mortality and attenuated thrombocytopenia associated with severe malaria in urokinase- and urokinase receptor-deficient mice.

We explored the role of urokinase and tissue-type plasminogen activators (uPA and tPA), as well as the uPA receptor (uPAR; CD87) in mouse severe malaria (SM), using genetically deficient (-/-) mice. The mortality resulting from Plasmodium berghei ANKA infection was delayed in uPA(-/-) and uPAR(-/-) mice but was similar to that of the wild type (+/+) in tPA(-/-) mice. Parasitemia levels were similar in uPA(-/-), uPAR(-/-), and +/+ mice. Production of tumor necrosis factor, as judged from the plasma level and the mRNA levels in brain and lung, was markedly increased by infection in both +/+ and uPAR(-/-) mice. Breakdown of the blood-brain barrier, as evidenced by the leakage of Evans Blue, was similar in +/+ and uPAR(-/-) mice. SM was associated with a profound thrombocytopenia, which was attenuated in uPA(-/-) and uPAR(-/-) mice. Administration of aprotinin, a plasmin antagonist, also delayed mortality and attenuated thrombocytopenia. Platelet trapping in cerebral venules or alveolar capillaries was evident in +/+ mice but absent in uPAR(-/-) mice. In contrast, macrophage sequestration in cerebral venules or alveolar capillaries was evident in both +/+ and uPAR(-/-) mice. Polymorphonuclear leukocyte sequestration in alveolar capillaries was similar in +/+ and uPAR(-/-) mice. These results demonstrate that the uPAR deficiency attenuates the severity of SM, probably by its important role in platelet kinetics and trapping. These results therefore suggest that platelet sequestration contributes to the pathogenesis of SM.

Chloroquine prophylaxis, iron/folic-acid supplementation or case management of malaria attacks in primigravidae in western Uganda: effects on congenital malaria and infant haemoglobin concentrations.

A randomized, double-blind, placebo-controlled trial, which compared the effects of three interventions (weekly chloroquine prophylaxis, daily iron and weekly folic-acid supplementation, and case management of malaria) on congenital malaria, maternal haemoglobin (Hb) and foetal outcome, was conducted among primigravidae resident in Hoima district, Uganda. Among 473 babies examined at birth or within 7 days of birth, 198 (42%) were parasitaemic, the level of parasitaemia in an infant being strongly correlated with those of placental (P< 0.01) and maternal, peripheral parasitaemia (P < 0.01). However, 33 (17%) of the parasitaemic babies were born to mothers who had placental but not peripheral parasitaemia, 22 (11%) to mothers who had peripheral but not placental parasitaemia, and 12 (6%) to mothers with neither peripheral nor placental parasitaemia. Overall, 163 babies were each examined for malarial parasites at birth and 1 month later. Of the 76 (47%) found to have parasitaemia at birth, 37 (23%) appeared aparasitaemic at the 1-month follow-up but 28 (17%) were still parasitaemic at that time. Among the babies born to the mothers who only received case management of malaria during pregnancy, parasitaemia at birth was associated with infant anaemia at birth (i.e. < 140 g Hb/litre; P = 0.03). Infants found to be parasitaemic at the 1-month follow-up had lower mean concentrations of Hb at that time than their aparasitaemic counterparts (P= 0.03). Parasitaemia at birth was not significantly associated with low birthweight, in any of three intervention groups. The intervention given to the mother had no significant effect on the parasitaemia of her baby, either at birth or at the age of 1 month. Congenital malaria per se may have little influence on birthweight but may have an impact on infant anaemia. In conclusion, congenital parasitaemia was not associated with birthweight, but was related to anaemia at birth in infants born to women who had only received active case management during their pregnancies.

[Malignant tropical malaria in native Africans living in a large city]. / Zlokachestvennaia tropicheskaia maliariia u korennykh afrikantsev, zhitelei krupnogo goroda.

The clinical and laboratory features of severe Plasmodium falciparum-induced malaria were analyzed in 91 adult patients living a large African city. Within a week, 52 patients developed the disease from the manifestations of overall intoxication to the complete picture of severe malaria accompanied by coma. Fifty eight patients were found to be residents of Conakry and 54 of them left the city 2 months before the malaria attack. Eighty one patients had experienced malaria, including 38 patients had 1-2 attacks in the past year. The patients were parenterally treated with quinine in a dose of 750-850 mg of the active ingredient for 24 hours during 4.1 +/- 1.7 days at hospital. In 17 of 34 patients, parasitemia disappeared from single to 5-10 parasites and more in the field of thick drop field, in the other 17 patients it decreased from 5-10 to single parasites at recovery. Twenty four comatose patients died at days 3-8 of hospital stay, most of them had symptoms of oligoanuria. The high cost of hospitalization and specific drugs were the reasons for late referral to hospital and for the use of low daily and course doses of quinine. The necessity of reviewing the principal trends of a national malaria control programme.