Immunohistopathological changes in the placenta of malaria-infected women in unstable transmission setting of Aligarh.

INTRODUCTION: Pregnant women are more susceptible to malaria due to a combination of physiological and immunological changes. The infection may even affect the growth and survival of the foetus, which mainly occur when parasite enters the placenta. The sequestration of infected erythrocytes may trigger the host response, leading to placental inflammation and altered development, affecting the structure and nutrient transport of placenta. These factors collectively impair placental functions and affect foetal growth. METHODS: Pregnant women with peripheral parasitaemia for P. falciparum and P. vivax (20 each) were included in the present study, along with 15 age-matched uninfected healthy pregnant women. Placentae were analysed for the presence of local parasitaemia along with pathological lesions caused due to the parasite. Immunohistochemical staining for CD20, CD45 and CD68 cells was performed for examining the specific leucocytes in the intervillous space of the placenta. RESULTS: Of the 20 individuals with P. falciparum, only seven placentae showed parasitaemia, whereas individuals with P. vivax showed no placental infection. The pathological changes observed in the P. falciparum-infected placenta include syncytial knotting, excess fibrinoid deposition, syncytiotrophoblast necrosis, syncytial rupture, thickening of trophoblast basement membrane and increased collagen deposition. Immunohistochemical staining showed a significant increase in B cells (CD20), leucocytes (CD45) and monocytes and macrophages (CD68) in the P. falciparum-infected placenta (p < 0.0001). DISCUSSION: The result implies that P. falciparum is responsible for pathological alterations in placenta, affecting the nutrient transport across placenta and foetal growth. The immune cells also migrate to the placenta and accumulate in the intervillous space to show humoral and cell-mediated immunity against the parasite.

Innate immune responses to malaria-infected erythrocytes in pregnant women: Effects of gravidity, malaria infection, and geographic location.

BACKGROUND: Malaria in pregnancy causes maternal, fetal and neonatal morbidity and mortality, and maternal innate immune responses are implicated in pathogenesis of these complications. The effects of malaria exposure and obstetric and demographic factors on the early maternal immune response are poorly understood. METHODS: Peripheral blood mononuclear cell responses to Plasmodium falciparum-infected erythrocytes and phytohemagglutinin were compared between pregnant women from Papua New Guinea (malaria-exposed) with and without current malaria infection and from Australia (unexposed). Elicited levels of inflammatory cytokines at 48 h and 24 h (interferon γ, IFN-γ only) and the cellular sources of IFN-γ were analysed. RESULTS: Among Papua New Guinean women, microscopic malaria at enrolment did not alter peripheral blood mononuclear cell responses. Compared to samples from Australia, cells from Papua New Guinean women secreted more inflammatory cytokines tumor necrosis factor-α, interleukin 1ß, interleukin 6 and IFN-γ; p<0.001 for all assays, and more natural killer cells produced IFN-γ in response to infected erythrocytes and phytohemagglutinin. In both populations, cytokine responses were not affected by gravidity, except that in the Papua New Guinean cohort multigravid women had higher IFN-γ secretion at 24 h (p = 0.029) and an increased proportion of IFN-γ+ Vδ2 γδ T cells (p = 0.003). Cytokine levels elicited by a pregnancy malaria-specific CSA binding parasite line, CS2, were broadly similar to those elicited by CD36-binding line P6A1. CONCLUSIONS: Geographic location and, to some extent, gravidity influence maternal innate immunity to malaria.

A novel murine model for assessing fetal and birth outcomes following transgestational maternal malaria infection.

Plasmodium falciparum infection during pregnancy is a major cause of severe maternal illness and neonatal mortality. Mouse models are important for the study of gestational malaria pathogenesis. When infected with Plasmodium chabaudi chabaudi AS in early gestation, several inbred mouse strains abort at midgestation. We report here that outbred Swiss Webster mice infected with P. chabaudi chabaudi AS in early gestation carry their pregnancies to term despite high parasite burden and malarial hemozoin accumulation in the placenta at midgestation, with the latter associated with induction of heme oxygenase 1 expression. Infection yields reduced fetal weight and viability at term and a reduction in pup number at weaning, but does not influence postnatal growth prior to weaning. This novel model allows for the exploration of malaria infection throughout pregnancy, modeling chronic infections observed in pregnant women prior to the birth of underweight infants and enabling the production of progeny exposed to malaria in utero, which is critical for understanding the postnatal repercussions of gestational malaria. The use of outbred mice allows for the exploration of gestational malaria in a genetically diverse model system, better recapitulating the diversity of infection responses observed in human populations.

Maternal, placental and cord blood cytokines and the risk of adverse birth outcomes among pregnant women infected with Schistosoma japonicum in the Philippines.

BACKGROUND: The objectives of this study were to 1) evaluate the influence of treatment with praziquantel on the inflammatory milieu in maternal, placental, and cord blood, 2) assess the extent to which proinflammatory signatures in placental and cord blood impacts birth outcomes, and 3) evaluate the impact of other helminths on the inflammatory micro environment. METHODS/FINDINGS: This was a secondary analysis of samples from 369 mother-infant pairs participating in a randomized controlled trial of praziquantel given at 12-16 weeks' gestation. We performed regression analysis to address our study objectives. In maternal peripheral blood, the concentrations of CXCL8, and TNF receptor I and II decreased from 12 to 32 weeks' gestation, while IL-13 increased. Praziquantel treatment did not significantly alter the trajectory of the concentration of any of the cytokines examined. Hookworm infection was associated with elevated placental IL-1, CXCL8 and IFN-γ. The risk of small-for-gestational age increased with elevated IL-6, IL-10, and CXCL8 in cord blood. The risk of prematurity was increased when cord blood sTNFRI and placental IL-5 were elevated. CONCLUSIONS: Our study suggests that fetal cytokines, which may be related to infectious disease exposures, contribute to poor intrauterine growth. Additionally, hookworm infection influences cytokine concentrations at the maternal-fetal interface. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE: ClinicalTrials.gov (NCT00486863).

Synergistic effect of DDT and its metabolites in lipopolysaccharide-mediated TNF-α production is inhibited by progesterone in peripheral blood mononuclear cells.

Increased TNF-α levels have been associated with adverse pregnancy outcomes. Lipopolysaccharide (LPS), 1,1,1-trichloro-2,2-bis-(chlorophenyl)ethane (DDT), 1,1-bis-(chlorophenyl)-2,2-dichloroethene (DDE), and 1,1-dichloro-2,2-bis(chlorophenyl)ethane (DDD) induce TNF-α release in peripheral blood mononuclear cells (PBMC). Conversely, progesterone (P4) inhibits TNF-α secretion. Pregnant women in malaria endemic areas may be co-exposure to these compounds. Thus, this study was to investigate the synergistic effect of LPS and these pesticides in PBMC and to assess P4 influence on this synergy. Cultured PBMC were exposed to each pesticide in the presence of LPS, P4, or their combination. TNF-α was measured by ELISA. All pesticides enhanced TNF-α synthesis in PBMC. Co-exposure with LPS synergizes TNF-α production, which is blocked by progesterone. These results indicate that these organochlorines act synergistically with LPS to induce TNF-α secretion in PBMC. This effect is blocked by P4.

Impact of In Utero Exposure to Malaria on Fetal T Cell Immunity.

Pregnancy-associated malaria, including placental malaria, causes significant morbidity and mortality worldwide. Recently, it has been suggested that in utero exposure of the fetus to malaria antigens may negatively impact the developing immune system and result in tolerance to malaria. Here, we review our current knowledge of fetal immunity to malaria, focusing on the dynamic interactions between maternal malaria infection, placental development, and the fetal immune system. A better understanding of the long-term impact of in utero malaria exposure on the development of natural immunity to malaria, immune responses to other childhood pathogens, and vaccine immunogenicity is urgently needed. This may guide the implementation of novel chemoprevention strategies during pregnancy and facilitate the push toward malaria vaccines.

Vertical transmission and fetal damage in animal models of congenital toxoplasmosis: A systematic review.

In humans, the probability of congenital infection and fetal damage due to Toxoplasma gondii is dependent on the gestation period at which primary infection occurs. Many animal models have been used for vaccine, drug testing, or studies on host or parasite factors that affect transmission or fetal pathology, but few works have directly tested fetal infection and damage rates along gestation. So, the purpose of this work was to perform a systematic review of the literature to determine if there is a model which reflects these changes as they occur in humans. We looked for papers appearing between 1970 and 2014 in major databases like Medline and Scopus, as well as gray literature. From almost 11,000 citations obtained, only 49 papers fulfilled the criteria of having data of all independent variables and at least one dependent datum for control (untreated) groups. Some interesting findings could be extracted. For example, pigs seem resistant and sheep susceptible to congenital infection. Also, oocysts cause more congenitally infected offspring than tissue cysts, bradyzoites or tachyzoites. In spite of these interesting findings, very few results on vertical transmission or fetal damage rates were similar to those described for humans and only for one of the gestation thirds, not all. Moreover, in most designs tissue cysts - with unknown number of bradyzoites - were used, so actual dose could not be established. The meta-analysis could not be performed, mainly because of great heterogeneity in experimental conditions. Nevertheless, results gathered suggest that a model could be designed to represent the increase in vertical transmission and decrease in fetal damage found in humans under natural conditions.

Differential roles of inflammation and apoptosis in initiation of mid-gestational abortion in malaria-infected C57BL/6 and A/J mice.

INTRODUCTION: Plasmodium chabaudi AS-infection in pregnant A/J and C57BL/6J mice results in mid-gestational pregnancy loss. Although associated with increased systemic and placental pro-inflammatory responses and coagulopathy, the molecular mechanisms that underlie poor pregnancy outcomes in these mice are not yet fully understood. This study investigates the relationships between inflammation, apoptosis and malaria-induced pregnancy loss. METHODS: Infection with P. chabaudi AS in early murine pregnancy and term human placental tissues from an endemic setting were assessed by histology, immunohistochemistry, TUNEL staining, real-time PCR, flow cytometry, western blot, and ELISA. RESULTS: Quantitative PCR reveals accumulation of lymphocytes and monocytes and upregulation of chemokines that attract these cell types in malaria-exposed mid-gestational A/J conceptuses. Monocyte accumulation is confirmed by flow cytometry and placental immunohistochemistry. Concurrent with initiation of malaria-induced abortion, markers of apoptosis are evident in the junctional zone, but not the labyrinth, of A/J placentae. In contrast, mid-gestation conceptuses in infected C57BL/6J lack evidence for monocyte accumulation, exhibiting low or no in situ placental staining despite trophoblast immunoreactivity for the monokine, CCL2. Additionally, placental apoptosis is not consistently observed, and when evident, appears after malaria-induced abortion typically initiates. Similarly, trophoblast apoptosis in term human placental malaria is not observed. Of those studied, a sole common feature of malaria-induced abortion in A/J and C57BL/6J mice is elevation of plasma tumor necrosis factor. DISCUSSION: Consistent with our previous observations, tumor necrosis factor is likely to be a central driver of malaria-induced pregnancy loss in both strains, but likely operates through mechanisms distinct from placental apoptosis in C57BL/6J mice.

Parasite accumulation in placenta of non-immune baboons during Plasmodium knowlesi infection.

BACKGROUND: Placental malaria (PM) causes adverse pregnancy outcomes in the mother and her foetus. It is difficult to study PM directly in humans due to ethical challenges. This study set out to bridge this gap by determining the outcome of PM in non-immune baboons in order to develop a non-human primate model for the disease. METHODS: Ten pregnant baboons were acquired late in their third trimester (day 150) and randomly grouped as seven infected and three non-infected. Another group of four nulligravidae (non-pregnant) infected was also included in the analysis of clinical outcome. Malaria infection was intravenously initiated by Plasmodium knowlesi blood-stage parasites through the femoral vein on 160(th) day of gestation (for pregnant baboons). Peripheral smear, placental smear, haematological samples, and histological samples were collected during the study period. Median values of clinical and haematological changes were analysed using Kruskal-Wallis and Dunn's Multiple Comparison Test. Parasitaemia profiles were analysed using Mann Whitney U test. A Spearman's rank correlation was run to determine the relationship between the different variables of severity scores. Probability values of P <0.05 were considered significant. RESULTS: Levels of white blood cells increased significantly in pregnant infected (34%) than in nulligravidae infected baboons (8%). Placental parasitaemia levels was on average 19-fold higher than peripheral parasitaemia in the same animal. Infiltration of parasitized erythrocytes and inflammatory cells were also observed in baboon placenta. Malaria parasite score increased with increase in total placental damage score (rs = 0.7650, P <0.05) and inflammatory score (rs = 0.8590, P <0.05). Although the sample size was small, absence of parasitized erythrocytes in cord blood and foetal placental region suggested lack of congenital malaria in non-immune baboons. CONCLUSION: This study has demonstrated accumulation of parasitized red blood cells and infiltration of inflammatory cells in the placental intravillous space (IVS) of baboons that are non-immune to malaria. This is a key feature of placental falciparum malaria in humans. This presents the baboon as a new model for the characterization of malaria during pregnancy.

Enterobius vermicularis salpingitis seen in the setting of ectopic pregnancy in a Malaysian patient.

We report a rare and unusual case of invasive Enterobius vermicularis infection in a fallopian tube. The patient was a 23-year-old Malaysian woman who presented with suprapubic pain and vaginal bleeding. A clinical diagnosis of ruptured right ovarian ectopic pregnancy was made. She underwent a laparotomy with a right salpingo-oophorectomy. Histopathological examination of the right fallopian tube showed eggs and adult remnants of E. vermicularis, and the results were confirmed using PCR and DNA sequencing.

Differential apoptosis in BeWo cells after infection with highly (RH) or moderately (ME49) virulent strains of Toxoplasma gondii is related to the cytokine profile secreted, the death receptor Fas expression and phosphorylated ERK1/2 expression.

INTRODUCTION: Alterations of apoptosis are commonly associated with pregnancy complications and abortion. Modulation of apoptosis is a relevant feature of Toxoplasma gondii infection and it is related to parasite strain types. The aim of the present study was to evaluate the possible factors that are involved in the differential apoptosis of BeWo cells infected with distinct T. gondii strain types. METHODS: Human trophoblastic cells (BeWo cell line) were infected with RH or ME49 strains, the cytokine production was measured and the phosphorylation of anti-apoptotic ERK1/2 protein was analyzed. Also, cells were treated with different cytokines, infected with RH or ME49 strain, and analyzed for apoptosis index and Fas/CD95 death receptor expression. RESULTS: ME49-infected BeWo cells exhibited a predominantly pro-inflammatory cytokine profile, whereas cells infected with RH strain had a higher production of anti-inflammatory cytokines. Also, the incidence of apoptosis was higher in ME49-infected cells, which have been treated with pro-inflammatory cytokines compared to cells infected with RH and treated with anti-inflammatory cytokines. Moreover, Fas/CD95 expression was higher in cells infected with either ME49 or RH strain and treated with pro-inflammatory cytokines compared to anti-inflammatory cytokine treatment. The phosphorylation of ERK1/2 protein increased after 24 h of infection only with the RH strain. CONCLUSION: These results suggest that opposing mechanisms of interference in apoptosis of BeWo cells after infection with RH or ME49 strains of T. gondii can be associated with the differential cytokine profile secreted, the Fas/CD95 expression and the phosphorylated ERK1/2 expression.

Placental infection with Plasmodium vivax: a histopathological and molecular study.

BACKGROUND: Evidence of the presence of Plasmodium vivax in the placenta is scarce and inconclusive. This information is relevant to understanding whether P. vivax affects placental function and how it may contribute to poor pregnancy outcomes. METHODS: Histopathologic examination of placental biopsies from 80 Papua New Guinean pregnant women was combined with quantitative polymerase chain reaction (qPCR) to confirm P. vivax infection and rule out coinfection with other Plasmodium species in placental and peripheral blood. Leukocytes and monocytes/macrophages were detected in placental sections by immunohistochemistry. RESULTS: Monoinfection by P. vivax and Plasmodium falciparum was detected by qPCR in 8 and 10 placentas, respectively. Seven of the 8 women with P. vivax placental monoinfection were negative in peripheral blood. By histology, 3 placentas with P. vivax monoinfection showed parasitized erythrocytes in the intervillous space but no hemozoin in macrophages nor increased intervillous inflammatory cells. In contrast, 7 placentas positive for P. falciparum presented parasites and hemozoin in macrophages or fibrin as well as intervillous inflammatory infiltrates. CONCLUSIONS: Plasmodium vivax can be associated with placental infection. However, placental inflammation is not observed in P. vivax monoinfections, suggesting other causes of poor delivery outcomes associated with P. vivax infection.

Plasmodium berghei: influence of infection on the oxidant and antioxidants levels in pregnant BALB/c mice.

Malarial infection during pregnancy has been associated with maternal anemia and death, abortion, still-birth and is a major cause of low birth weight, an important risk factor for infant morbidity and mortality in endemic areas. The present study was designed to delineate the oxidative stress in various organs (liver, spleen, kidney, brain and placenta) of pregnant Plasmodium berghei infected BALB/c mice. It was observed that pregnant-infected mice had higher parasitaemia than nonpregnant-infected mice. Most notably, levels of malondialdehyde (MDA), a measure of lipid peroxidation, reduced glutathione (GSH) and superoxide dismutase (SOD) levels were significantly higher in the liver, spleen, kidney and brain of pregnant-infected mice compared with pregnant mice. Although MDA levels were significantly higher, GSH and SOD levels remained unaltered in the placenta of pregnant-infected mice compared with pregnant mice. Furthermore, catalase activity was significantly lower in all the organs of pregnant-infected mice compared with pregnant mice. Histopathological observations in the organs clearly show the cellular and morphological alterations that may be occurring due to increased lipid peroxidation. Taken together, the data suggest that the increased severity of malarial infection during pregnancy may be due to accentuated oxidative stress.

Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study.

BACKGROUND: The effects of malaria and its treatment in the first trimester of pregnancy remain an area of concern. We aimed to assess the outcome of malaria-exposed and malaria-unexposed first-trimester pregnancies of women from the Thai-Burmese border and compare outcomes after chloroquine-based, quinine-based, or artemisinin-based treatments. METHODS: We analysed all antenatal records of women in the first trimester of pregnancy attending Shoklo Malaria Research Unit antenatal clinics from May 12, 1986, to Oct 31, 2010. Women without malaria in pregnancy were compared with those who had a single episode of malaria in the first trimester. The association between malaria and miscarriage was estimated using multivariable logistic regression. FINDINGS: Of 48,426 pregnant women, 17,613 (36%) met the inclusion criteria: 16,668 (95%) had no malaria during the pregnancy and 945 (5%) had a single episode in the first trimester. The odds of miscarriage increased in women with asymptomatic malaria (adjusted odds ratio 2·70, 95% CI 2·04-3·59) and symptomatic malaria (3·99, 3·10-5·13), and were similar for Plasmodium falciparum and Plasmodium vivax. Other risk factors for miscarriage included smoking, maternal age, previous miscarriage, and non-malaria febrile illness. In women with malaria, additional risk factors for miscarriage included severe or hyperparasitaemic malaria (adjusted odds ratio 3·63, 95% CI 1·15-11·46) and parasitaemia (1·49, 1·25-1·78 for each ten-fold increase in parasitaemia). Higher gestational age at the time of infection was protective (adjusted odds ratio 0·86, 95% CI 0·81-0·91). The risk of miscarriage was similar for women treated with chloroquine (92 [26%] of 354), quinine (95 [27%) of 355), or artesunate (20 [31%] of 64; p=0·71). Adverse effects related to antimalarial treatment were not observed. INTERPRETATION: A single episode of falciparum or vivax malaria in the first trimester of pregnancy can cause miscarriage. No additional toxic effects associated with artesunate treatment occurred in early pregnancy. Prospective studies should now be done to assess the safety and efficacy of artemisinin combination treatments in early pregnancy.

Human hydatidosis in Tehran, Iran: a retrospective epidemiological study of surgical cases between 1999 and 2009 at two university medical centers.

This study was conducted to evaluate retrospectively 203 patients diagnosed with hydatid cyst disease and treated surgically at two university medical centers between 1999 and 2009 in Tehran, the capital of Iran. Cystic echinococcosis (CE) affected more females 117 (57.6%) than males 86 (42.4%). A remarkable gender difference skewed towards females was observed, and the male/female ratio among CE cases ≤20 and ≥61 years old was 1.18 and 0.52, respectively. The age of the patients ranged from 8 to 82 years, and the age group 21-40 years (42.8%) was the most affected. A significantly higher number of hydatid cysts were recorded in the liver than in other sites (P<0.001), and more females had higher hepatic cysts (48.8%) than males (35.0%). The ratio of hepatic hydatidosis to pulmonary hydatidosis was about 11. There was a relative direct relationship between the ratio of liver to lung cases and age, and this ratio was significantly (P<0.01) higher in individuals >40 years of age (liver/lung ratio ≥43) than in those <40 years of age (liver/lung ratio 2.8-7.6). Unusual cyst locations in kidneys, brain and pelvic area, followed by spleen and spine was also observed. Single organ involvement was found in 95% of the patients, and was more common in females (55.2%) than in males (39.9%). Housewives had the highest rate of infection (53.5%) followed by labourers with 14.8%, which showed a significant difference (P<0.001). Similarly, urban dwellers was also over-represented among the cases (87% urban vs. 13% rural; P<0.001). In 69.5% of cases there was only one cyst, 16.3% had two cysts, 4.7% with three cysts, and 9.5% had four cysts or more. The results showed that further studies are needed to determine the prevalence, economic impact and risk factors of the disease in the area.

[Early stage of Acanthamoeba keratitis]. / Tidligt stadie af akantamøbekeratitis.

We present a case of early detected Acanthamoeba keratitis. The patient was a 31 year-old female with keratitis who was referred to our clinic. Upon arrival the patient presented with subepithelial corneal infiltrates and radiating neuritis. In vivo confocal microscopy showed Acanthamoeba cysts and treatment was initiated. Polymerase chain reaction analysis later confirmed the diagnosis and after three months symptoms had abated and vision was 1.0 (6/6). We confirm that an early diagnosis af Acanthamoeba keratitis is pivotal.

Maternal Schistosomiasis japonica is associated with maternal, placental, and fetal inflammation.

Schistosomes infect ∼40 million women of childbearing age and result in the elaboration of proinflammatory cytokines that have been implicated in fetal growth restriction. In murine models and two observational studies in humans, schistosome infection during pregnancy was associated with reduced birth weight, although a recent treatment trial in Schistosoma mansoni did not detect this association. We conducted an observational study among 99 pregnant women living in an area of Schistosoma japonicum endemicity in the Philippines. We enrolled women at 32 weeks gestation and measured S. japonicum and geohelminth infection intensity. We collected maternal peripheral blood at 32 weeks gestation and placental and cord blood at delivery to assess inflammatory status. At delivery, we collected a placental-tissue sample and measured birth weight. In multivariate models adjusted for geohelminths, maternal schistosomiasis was associated with increased levels of inflammatory cytokines in maternal peripheral (tumor necrosis factor alpha [TNF-α] and interleukin 10 [IL-10]), placental (TNF-α, IL-6, TNF-α receptor II [RII], and IL-1ß), and cord (IL-1ß and TNF-α RII) blood, as well as acute subchorionitis and increased TNF-α production by syncytiotrophoblasts assessed by immunohistochemistry (all P < 0.05). After adjusting for confounders, placental IL-1ß, and TNF-α production by syncytiotrophoblasts was independently associated with decreased birth weight (both P < 0.05). Our data indicate that maternal schistosomiasis results in a proinflammatory signature that is detectable in maternal, placental, and fetal compartments, and a subset of these responses are associated with decreased birth weight. This potential mechanistic link between maternal schistosomiasis and poor birth outcomes will contribute to the debate regarding treatment of maternal schistosome infections.

Elevated levels of soluble TNF receptors 1 and 2 correlate with Plasmodium falciparum parasitemia in pregnant women: potential markers for malaria-associated inflammation.

Plasmodium falciparum-infected erythrocytes (IEs) sequester in the intervillous space (IVS) of the placenta causing placental malaria (PM), a condition that increases a woman's chances of having a low-birth-weight baby. Because IEs sequester, they frequently are not observed in peripheral blood smears, resulting in women with PM being misdiagnosed and thus not treated. Because sequestered IEs induce inflammation in the IVS, detection of inflammatory mediators in the peripheral blood may provide an approach for diagnosing PM. Two counterregulatory molecules, TNF-αR (TNFR) 1 and TNFR2, modulate the pathological effects of TNF-α. Levels of these soluble TNFRs (sTNFRs) are reported to be elevated in children with severe malaria, but it is unclear if they are increased in the peripheral blood of PM-positive women with asymptomatic infections. In this study, sTNFR levels were measured throughout the course of pregnancy, as well as at delivery, in women with asymptomatic infections and those who remained uninfected. Results showed that both sTNFRs were significantly increased in the peripheral blood of women with asymptomatic malaria (p < 0.0001) and were positively correlated with parasitemia (p < 0.0001 for sTNFR1 and p = 0.0046 for sTNFR2). Importantly, levels of sTNFR2 were elevated in the peripheral blood of women who were PM-positive but peripheral blood-smear negative (p = 0.0017). Additionally, sTNFR2 levels were elevated in the blood of malaria-positive women who delivered low-birth-weight babies. In vitro studies demonstrated that syncytiotrophoblasts were not a major source of sTNFR. These data suggest that sTNFR2 may be a valuable biomarker for detection of malaria-associated inflammation.

Effects of Neospora caninum infection at mid-gestation on placenta in a pregnant mouse model.

Neospora caninum is one of the more-efficient transplacentally-transmitted organisms. The goal of the present study was to investigate the pathologic and immunologic changes that occur at the materno-fetal interphase in pregnant BALB/c mice infected with N. caninum at mid-gestation. Parasite DNA was detected in feto-placentary units 3 days post-infection (PI). On day 7 PI, the DNA detection level and parasite burden were significantly higher in the placentas than in the fetuses, which may indicate that the parasite is mainly multiplying in the placenta during the initial infection. In the spleens of infected dams, we observed an increase in IFN-γ, IL-10, and IL-4. However, only IL-4 was upregulated in placentas from the infected dams; this may enhance susceptibility to N. caninum at the materno-fetal interphase and favor transmission to the progeny. Finally, an increase in TNF-α expression in nested-PCR-positive placentas combined with necrosis may compromise the viability of the fetuses.