Synergy of Omeprazole and Praziquantel In Vitro Treatment against Schistosoma mansoni Adult Worms

BackgroundTreatment and morbidity control of schistosomiasis relies on a single drug, praziquantel (PZQ), and the selection of resistant worms under repeated treatment is a concern. Therefore, there is a pressing need to understand the molecular effects of PZQ on schistosomes and to investigate alternative or synergistic drugs against schistosomiasis.MethodologyWe used a custom-designed Schistosoma mansoni expression microarray to explore the effects of sublethal doses of PZQ on large-scale gene expression of adult paired males and females and unpaired mature females. We also assessed the efficacy of PZQ, omeprazole (OMP) or their combination against S. mansoni adult worms with a survival in vitro assay.ConclusionsFunctional analysis of gene interaction networks is an important approach that can point to possible novel synergistic drug candidates. We demonstrated the potential of this strategy by showing that PZQ in combination with OMP displayed increased efficiency against S. mansoni adult worms in vitro when compared with either drug alone.     

Immune Effects of Nonylphenol on Offspring of Rats Exposed During Pregnancy

Effects of nonylphenol on immune system of male rats were examined. Dams were treated orally with nonylphenol at doses of 0, 20, 40, 80, or 200 mg/kg, respectively, from pregnant days 14 to 19. The offspring rats were investigated at postnatal day 60. Compared with the control groups, the doses of 80 and 200 mg nonylphenol/kg induced an obvious decrease in the absolute and relative weight of spleen and thymus. In the 200 mg/kg nonylphenol-treated group, the proliferative responses of murine spleen lymphocytes cultured in vitro were suppressed, Cytokine productions of interferon-gamma and interleukin-6 in serum were markedly lower than those in the control group. Histologically, the boundary between splenic red pulp and white pulp was unclear, expansion and congestion appeared in splenic sinus, lymphocytes in spleen and thymus dramatically reduced, and lots of focal necrosis cells were present. The results of this study show that nonylphenol can cross the placenta barrier, and that in utero exposure to 200 mg/kg/day nonylphenol can inhibit immune function in male offspring rats.     

Prevalence of Intestinal Parasitic Infections among Children under Five Years of Age with Emphasis on Schistosoma mansoni in Wonji Shoa Sugar Estate,Ethiopia

Intestinal parasite infections are major public health problems of children in developing countries causing undernutrition, anemia, intestinal obstruction and mental and physical growth retardation. This study was conducted to assess the prevalence of intestinal helminthic infections among children under five years of age with emphasis on Schistosoma mansoni in Wonji Shoa Sugar Estate, Ethiopia. A cross-sectional parasitological survey was conducted in under-five children living in Wonji Shoa Sugar Estate Ethiopia, April, 2013. Stool samples were collected and examined for intestinal parasites using single Kato-Katz and single Sodium acetate-acetic acid-formalin (SAF) solution concentration methods. Out of 374 children examined using single Kato-Katz and single SAF-concentration methods, 24.3% were infected with at least one intestinal parasite species. About 10.4%, 8.8%, 4.6%, 2.9%, 1.6% and 0.8% of the children were infected with Hymenolepis nana, Schistosoma mansoni, Ascaris lumbricoides, Trichuris trichiura, Enterobius vermicularis and hookworm, respectively. Prevalence of double, triple and quadruple intestinal helminthic infection was 6.4%, 0.54% and 1.1%, respectively. A significant increase in prevalence of S. mansoni (8.3% versus 3.2%) and T. trichiura (2.7% versus 0.5%) infection was observed when determined via the single Kato-Katz method compared to the prevalence of the parasites determined via the single SAF-concentration method. On the other hand, the single SAF-concentration method (9.1%) revealed a significantly higher prevalence of H. nana infection than the single Kato-Katz (1.6%) does. In conclusion, intestinal helminths infections particularly S. mansoni and H. nana were prevalent in under-five children of Wonji Shoa Sugar Estate. Including praziquantel treatment in the deworming program as per the World Health Organization guidelines would be vital to reduce the burden of these diseases in areas where S. mansoni and H. nana infections are prevalent among under-fives. Kato-Katz can be used in estimating the prevalence of S. mansoni and other helminth infections.     

Effects of Gestational Cadmium Exposure on Pregnancy Outcome and Development in the Offspring at Age 4.5 Years

The objective of the present study was to evaluate the potential effect of maternal cadmium exposure on pregnancy outcome and development in the offspring at age 4.5 years. Between November 2002 and December 2003, 109 normal pregnant women were enrolled in our cohort from Da-Ye Country, Hubei Province in Central China. The placental, whole blood, and cord blood levels of cadmium were determined by inductively coupled plasma mass spectrometer (ICP-MS). The 106 children at 4.5 years of age given birth by the aforementioned women were followed up and the following rate was 97.25%. Detailed questionnaire surveys, anthropometric measurements were performed, and IQ development was evaluated by Wechsler Preschool and Primary Scale of Intelligence Revised Edition (WPPSI-R). Multiple linear regression analysis indicated that cord blood cadmium level was significantly negatively correlated with fetus development. Low birth weight (less than 2,500 g) occurred significantly more frequently in infants with higher cord blood cadmium than in those exposed to lower levels of cord blood cadmium. Significantly negative correlation was found between cord blood cadmium exposure and WPPSI-R IQ full score after controlling for confounding variables. It was concluded that cord blood cadmium concentration was a factor that influenced fetus growth and later IQ development.     

Maternal Insulin Sensitivity During Pregnancy Predicts Infant Weight Gain and Adiposity at 1 Year of Age

Emerging evidence suggests that fetal environmental exposures impact on future development of obesity. The objectives of this study were to assess the relationships between (i) maternal insulin sensitivity and glucose tolerance status in pregnancy and (ii) early infant weight gain and adiposity in the first year of life. In this prospective cohort study, 301 women underwent oral glucose tolerance testing for assessment of glucose tolerance status and insulin sensitivity (IS_OGTT) in pregnancy. Their infants underwent anthropometric assessment at 12 months of age, including determination of weight gain in the first year of life and sum of skinfold thickness (SFT), a measure of infant adiposity. Infant weight gain and sum of SFT at 12 months did not differ according to maternal glucose tolerance status. On univariate analyses, weight gain from 0 to 12 months and sum of SFT were negatively associated with maternal IS_OGTT during pregnancy. On multiple linear regression analysis, negative independent predictors of weight gain from 0 to 12 months were maternal IS_OGTT during pregnancy (t = ?2.73; P = 0.007), infant female gender (t = ?3.16; P = 0.002), and parental education (t = ?1.98; P = 0.05), whereas white ethnicity was a positive independent predictor (t = 2.68; P = 0.008). Maternal IS_OGTT (t = ?2.7; P = 0.008) and parental education (t = ?2.58; P = 0.01) were independent negative predictors of sum of SFT at 12 months. Independent of maternal glucose tolerance status, maternal insulin resistance during pregnancy is associated with increased infant weight gain and adiposity over the first year of life. Further longitudinal study to evaluate obesity in this group of children will increase our understanding of the contribution of the intrauterine environment to their long‐term health.     

Metabolic Profile in Early Pregnancy Is Associated with Offspring Adiposity at 4 Years of Age: The Rhea Pregnancy Cohort Crete,Greece

ContextMaternal pre-pregnancy obesity may increase the risk of childhood obesity but it is unknown whether other metabolic factors in early pregnancy such as lipid profile and hypertension are associated with offspring cardiometabolic traits.ObjectiveOur objective was to investigate whether fasting lipid, glucose, and insulin levels during early pregnancy and maternal pre-pregnancy weight status, are associated with offspring adiposity measures, lipid levels and blood pressure at preschool age.ResultsPre-pregnancy overweight/obesity was associated with greater risk of offspring overweight/obesity (RR: 1.83, 95%CI: 1.19, 2.81), central adiposity (RR: 1.97, 95%CI: 1.11, 3.49), and greater fat mass by 5.10mm (95%CI: 2.49, 7.71) at 4 years of age. These associations were more pronounced in girls. An increase of 40mg/dl in fasting serum cholesterol levels in early pregnancy was associated with greater skinfold thickness by 3.30mm (95%CI: 1.41, 5.20) at 4 years of age after adjusting for pre-pregnancy BMI and several other confounders. An increase of 10mmHg in diastolic blood pressure in early pregnancy was associated with increased risk of offspring overweight/obesity (RR: 1.22, 95%CI: 1.03, 1.45), and greater skinfold thickness by 1.71mm (95% CI: 0.57, 2.86) at 4 years of age.ConclusionsMetabolic dysregulation in early pregnancy may increase the risk of obesity at preschool age.     

The Effect of Maternal Helminth Infection on Maternal and Neonatal Immune Function and Immunity to Tuberculosis

Background

M. tuberculosis and helminth infection each affects one third of the world population. Helminth infections down regulate cell mediated immune responses and this may contribute to lower efficacy of BCG vaccination and higher prevalence of tuberculosis.

Objective

To determine the effect of maternal helminth infection on maternal and neonatal immune function and immunity to TB.

Methods

In this cross sectional study, eighty five pregnant women were screened for parasitic and latent TB infections using Kato-Katz and QFT-GIT tests, respectively. IFN-γ and IL-4 ELISpot on Cord blood Mononuclear Cells, and total IgE and TB specific IgG ELISA on cord blood plasma was performed to investigate the possible effect of maternal helminth and/or latent TB co-infection on maternal and neonatal immune function and immunity to TB.

Result

The prevalence of helminth infections in pregnant women was 27% (n = 23), with Schistosoma mansoni the most common helminth species observed (20% of women were infected). Among the total of 85 study participants 25.8% were QFT-GIT positive and 17% had an indeterminate result. The mean total IgE value of cord blood was significantly higher in helminth positive than negative women (0.76 vs 0.47, p = 0.042). Cross placental transfer of TB specific IgG was significantly higher in helminth positive (21.9±7.9) than negative (12.3±5.1), p = 0.002) Latent TB Infection positive participants. The IFN-γ response of CBMCs to ESAT-6/CFP-10 cocktail (50 vs 116, p = 0.018) and PPD (58 vs 123, p = 0.02) was significantly lower in helminth positive than negative participants. There was no significant difference in IL-4 response of CBMCs between helminth negative and positive participants.

Conclusions

Maternal helminth infection had a significant association with the IFN-γ response of CBMCs, total IgE and cross placental transfer of TB specific IgG. Therefore, further studies should be conducted to determine the effect of these factors on neonatal immune response to BCG vaccination.     

Maternal Undernutrition During Lactation: Effect on Amino Acids in Brain Regions of Offspring

Sprague-Dawley dams were fed either a protein-calorie deficient or control diet from day 5 to day 21 after parturition. The concentrations of seven amino acids (aspartate, glutamate, gamma-aminobutyric acid, glycine, glutamine, serine, and taurine) were determined in brain regions from 17-day-old undernourished offspring and from 35-day-old rehabilitated rats. The brain regions examined were the cortex, cerebellum, corpus striatum, hippocampus, hypothalamus, brainstem, and midbrain. At 17 days of age, taurine was the amino acid with the highest concentration, whereas at 35 days glutamate had the highest concentration. This change was due to the fact that the concentration of taurine decreased significantly in all brain regions between 17 and 35 days, whereas the concentration of glutamate remained high or increased somewhat in all brain regions except the hypothalamus and brainstem. When the age-matched offspring of control and undernourished rats were compared, several interesting and significant differences were found. The concentrations of glutamate and aspartate were significantly lower (decreased 16-34%) in the cerebellum, brainstem, cortex, and midbrain in 17-day-old undernourished rats. The aspartate level was also significantly decreased in the corpus striatum and hypothalamus in 17-day-old offspring. However, the deficiencies of aspartate and glutamate were transient and reversible. In contrast, the concentration of taurine was increased in the hypothalamus (31%) and hippocampus (12-33%) at both 17 and 35 days of age and in the midbrain (17%) at 17 days. Other transient abnormalities in amino acid levels were found in undernourished offspring. The results of these experiments suggest that undernutrition during lactation causes delayed CNS development, which is manifested in altered concentrations of the neurotransmitters aspartate, glutamate, and taurine.     

Influence of Schistosoma mansoni and Hookworm Infection Intensities on Anaemia in Ugandan Villages

BackgroundThe association of anaemia with intestinal schistosomiasis and hookworm infections are poorly explored in populations that are not limited to children or pregnant women.MethodsWe sampled 1,832 individuals aged 5–90 years from 30 communities in Mayuge District, Uganda. Demographic, village, and parasitological data were collected. Infection risk factors were compared in ordinal logistic regressions. Anaemia and infection intensities were analyzed in multilevel models, and population attributable fractions were estimated.FindingsHousehold and village-level predictors of Schistosoma mansoni and hookworm were opposite in direction or significant for single infections. S. mansoni was found primarily in children, whereas hookworm was prevalent amongst the elderly. Anaemia was more prevalent in individuals with S. mansoni and increased by 2.86 fold (p-value<0.001) with heavy S. mansoni infection intensity. Individuals with heavy hookworm were 1.65 times (p-value = 0.008) more likely to have anaemia than uninfected participants. Amongst individuals with heavy S. mansoni infection intensity, 32.0% (p-value<0.001) of anaemia could be attributed to S. mansoni. For people with heavy hookworm infections, 23.7% (p-value = 0.002) of anaemia could be attributed to hookworm. A greater fraction of anaemia (24.9%, p-value = 0.002) was attributable to heavy hookworm infections in adults (excluding pregnant women) as opposed to heavy hookworm infections in school-aged children and pregnant women (20.2%, p-value = 0.001).ConclusionCommunity-based surveys captured anaemia in children and adults affected by S. mansoni and hookworm infections. For areas endemic with schistosomiasis or hookworm infections, WHO guidelines should include adults for treatment in helminth control programmes.     

Revisiting the Effect of Maternal Smoking during Pregnancy on Offspring Birthweight: A Quasi-Experimental Sibling Analysis in Sweden

Maternal smoking during pregnancy (SDP) seems associated with reduced birthweight in the offspring. This observation, however, is based on conventional epidemiological analyses, and it might be confounded by unobserved maternal characteristics related to both smoking habits and offspring birth weight. Therefore, we apply a quasi-experimental sibling analysis to revisit previous findings. Using the Swedish Medical Birth Register, we identified 677,922 singletons born between 2002 and 2010 from native Swedish mothers. From this population, we isolated 62,941 siblings from 28,768 mothers with discrepant habits of SDP. We applied conventional and mother-specific multilevel linear regression models to investigate the association between maternal SDP and offspring birthweight. Depending on the mother was light or heavy smoker and the timing of exposition during pregnancy (i.e., first or third trimester), the effect of smoking on birthweight reduction was between 6 and 78 g less marked in the sibling analysis than in the conventional analysis. Sibling analysis showed that continuous smoking reduces birthweight by 162 grams for mothers who were light smokers (1 to 9 cigarettes per day) and 226 g on average for those who were heavy smokers throughout the pregnancy in comparison to non-smoker mothers. Quitting smoking during pregnancy partly counteracted the smoking-related birthweight reduction by 1 to 29 g, and a subsequent smoking relapse during pregnancy reduced birthweight by 77 to 83 g. The sibling analysis provides strong evidence that maternal SDP reduces offspring birthweight, though this reduction was not as great as that observed in the conventional analysis. Our findings support public health interventions aimed to prevent SDP and to persuade those who already smoke to quit and not relapse throughout the pregnancy. Besides, further analyses are needed in order to explain the mechanisms through which smoking reduces birthweight and to identify other maternal characteristics that are common causes of both birthweight reduction and maternal smoking.     

根田鼠母体捕食应激对其雌性子代雄性化效应的研究

本研究了根田鼠母体捕食应激对其雌性子代雄性化的效应。母体捕食应激使雌性子代在鼻端探究、生殖区探究、试图探究和爬跨及尾随等性行为中花费的时间最多,阴道开口时间显延迟,生殖器与肛门间距离显增大,而母体食物限制和断乳应激子代则未明显呈现上述特征。母体捕食应激使其雌性子代显地降低对雄性个体的性吸引力。因此,母体捕食应激使雌性子代在性行为、形态特征及性吸引力方面呈现雄性化效应,主要归结于捕食应激引起母体内分泌的改变所致;此效应仅产生于胚胎性分化的特定关键时期。全结果检验了田鼠类母体捕食应激对其雌性子代性分化有显影响的假设。     

Risk Factors and Spatial Distribution of Schistosoma mansoni Infection among Primary School Children in Mbita District,Western Kenya

Background

An increasing risk of Schistosoma mansoni infection has been observed around Lake Victoria, western Kenya since the 1970s. Understanding local transmission dynamics of schistosomiasis is crucial in curtailing increased risk of infection.

Methodology/Principal Findings

We carried out a cross sectional study on a population of 310 children from eight primary schools. Overall, a total of 238 (76.8%) children were infected with S. mansoni, while seven (2.3%) had S. haematobium. The prevalence of hookworm, Trichuris trichiura and Ascaris lumbricoides were 6.1%, 5.2% and 2.3%, respectively. Plasmodium falciparum was the only malaria parasite detected (12.0%). High local population density within a 1 km radius around houses was identified as a major independent risk factor of S. mansoni infection. A spatial cluster of high infection risk was detected around the Mbita causeway following adjustment for population density and other potential risk factors.

Conclusions/Significance

Population density was shown to be a major factor fuelling schistosome infection while individual socio-economic factors appeared not to affect the infection risk. The high-risk cluster around the Mbita causeway may be explained by the construction of an artificial pathway that may cause increased numbers of S. mansoni host snails through obstruction of the waterway. This construction may have, therefore, a significant negative impact on the health of the local population, especially school-aged children who frequently come in contact with lake water.     

Associations of Maternal Iron Intake and Hemoglobin in Pregnancy with Offspring Vascular Phenotypes and Adiposity at Age 10: Findings from the Avon Longitudinal Study of Parents and Children

Background

Iron deficiency is common during pregnancy. Experimental animal studies suggest that it increases cardiovascular risk in the offspring.

Objective

To examine the relationship between maternal pregnancy dietary and supplement iron intake and hemoglobin, with offspring’s arterial stiffness (measured by carotid-radial pulse wave velocity), endothelial function (measured by brachial artery flow mediated dilatation), blood pressure, and adiposity (measured by body mass index), test for mediation by cord ferritin, birth weight, gestational age, and child dietary iron intake, and for effect modification by maternal vitamin C intake and offspring sex.

Design

Prospective data from 2958 mothers and children pairs at 10 years of age enrolled in an English birth cohort, the Avon Longitudinal Study for Parents and Children (ALSPAC), was analysed.

Results

2639 (89.2%) mothers reported dietary iron intake in pregnancy below the UK reference nutrient intake of 14.8 mg/day. 1328 (44.9%) reported taking iron supplements, and 129 (4.4%) were anemic by 18 weeks gestation. No associations were observed apart from maternal iron intake from supplements with offspring systolic blood pressure (−0.8 mmHg, 99% CI −1.7 to 0, P = 0.01 in the sample with all relevant data observed, and −0.7 mmHg, 99% CI −1.3 to 0, P = 0.008 in the sample with missing data imputed).

Conclusion

There was no evidence of association between maternal pregnancy dietary iron intake, or maternal hemoglobin concentration (which is less likely to be biased by subjective reporting) with offspring outcomes. There was a modest inverse association between maternal iron supplement intake during pregnancy with offspring systolic blood pressure at 10 years.     

Effect of closantel on intrategumental pH in Schistosoma mansoni and Fasciola hepatica

It has been proposed that the anthelmintic activity of the flukicide, closantel, is due to the drug's ability to interfere with the proton gradient in the parasite's mitochondria that in turn inhibits the generation of ATP by the parasite. Recent results using 31P-NMR suggest that this is not the primary target of the drug. We measured the effects of closantel on fluke intrategumental pH and observed a significant decrease (6.8 to 6.5). This decrease occurred within 10 min and at concentrations that were lower than those that produced significant changes in parasite ATP concentration. We also noted that this drug-induced change in intrategumental pH was associated with a marked reduction in fluke motility. Our results, when coupled to previous reports, would suggest that closantel is a membrane-active molecule that is capable of affecting a number of helminth biochemical and physiological processes.     

Prevalence and Predictors of Malnutrition among Guatemalan Children at 2 Years of Age

ObjectiveTo identify the prevalence and predictors of malnutrition among 2-year old children in the Western Highlands of Guatemala.MethodsProspective cohort of 852 Guatemalan children in San Lucas Toliman, Guatemala followed from birth to age 2 from May 2008 to December 2013. Socio-demographic, anthropometric, and health data of children was collected at 2 month intervals.ResultsAmong the 402 males and 450 females in the cohort, mean weight-for-age Z-score (WAZ) declined from -0.67 ± 1.01 at 1 year to -1.07 ± 0.87 at 2 years, while mean height-for-age Z-score (HAZ) declined from -1.88 ± 1.19 at 1 year to -2.37 ± 0.99 at 2 years. Using multiple linear regression modeling, number of children <5 years old, vomiting in the past week, fever in the past week, and WAZ at 1 year were significant predictors of WAZ at 2 years. Significant predictors of HAZ at 2 years included household size, number of children <5 years old, diarrhea in the past week, WAZ at 1 year, and HAZ at 1 year. Vomiting in the past week and WAZ at 1 year were significant predictors of weight-for-height z-score (WHZ) at 2 years.ConclusionsNumber of children <5 years old, symptoms such as vomiting or diarrhea in the previous week, and prior nutritional status were the most significant predictors of malnutrition in this cohort. Future research may focus on the application of models to develop predictive algorithms for mobile device technology, as well as the identification of other predictors of malnutrition that are not well characterized such as the interaction of environmental exposures with protein consumption and epigenetics.     

Praziquantel has no direct effect on (Na++K+)-ATPases and (Ca2+-Mg2+)ATPases of Schistosoma mansoni

Therapeutic concentrations of praziquantel produce a rapid and intense contraction of the human flatworm Schistosoma mansoni. As an action on ATPases responsible for calcium homeostasis arises as a possible explanation for the molecular mechanism of this effect, we tested here the effect of praziquantel on different preparations from male adult worms that were previously characterized for their content in (Na⁺+K⁺)-ATPase and (Ca²⁺-Mg²⁺)ATPase activities from different origins. Concentrations as high as 100 μM praziquantel did not inhibit (Na⁺+K⁺)-ATPase from tegument and carcass nor (Ca²⁺-Mg ²⁺)ATPase from heterogeneous (P₁) and microsomal (P₄) fractions. As 100 μM praziquantel was also without effect on calcium permeability of microsomal vesicles actively loaded with ⁴⁵Ca²⁺, the present results discard three hypotheses recently raised for the mechanism of praziquantel-induced contraction of S. mansoni.     

Effect of ultraviolet radiation on survival, infectivity and maturation of Schistosoma mansoni cercariae

S. mansoni cercariae exposed to ultraviolet radiation for 1, 3, 5, 10 and 20 s as well as non-irradiated cercariae remained actively motile 30 min post-irradiation. Thereafter the activity decreased with increasing dose level of radiation and age of cercariae. There was no significant difference between the rates of attachment of the batches of cercariae. The recovery rates (0-49% of cercariae to which mice were exposed) of adult worms were, however, significantly different from the number of cercariae calculated to have attached to the mice (93.5-100% of cercariae to which mice were exposed). Maturation and penetration rates were dependent on radiation exposure levels. Numbers of eggs deposited in the liver of mice as well as hatchability rate of eggs varied significantly with the levels of exposure to radiation.