Evidence for an improvement in cognitive function following treatment of Schistosoma japonicum infection in Chinese primary schoolchildren.

A double-blind, placebo-controlled, treatment trial was conducted in Sichuan, China to investigate the unique and combined effects on the cognitive function (working memory) of children after treating geohelminth infections with albendazole and treating Schistosoma japonicum infection with praziquantel. One hundred eighty-one children 5-16 years of age participated. At baseline, the praziquantel and placebo groups were similar in all background characteristics. Three months after praziquantel treatment, there was a significant reduction in the prevalence and intensity of S. japonicum infection. There were significant age group by praziquantel treatment interaction effects in three of the five cognitive tests, Fluency, Picture Search, and Free Recall, with effects being strongest in the youngest children (5-7 years old). Exploratory analysis within the youngest children showed a significant positive main effect of treatment on Fluency (P < 0.001), after controlling for sex, anthropometric, and parasitic and iron status. There was also a treatment by height-for-age interaction (P = 0.03) and a treatment by iron status interaction (P = 0.024) on Fluency. There was a treatment by S. japonicum intensity interaction (P < 0.001) on Free Recall, but the main effect of treatment on Picture Search was not significant (P = 0.058). Younger children and those who are physically the most vulnerable are likely to benefit the most from the treatment of S. japonicum infection in terms of improved performance on tests of working memory.

Double-blind placebo-controlled study of concurrent administration of albendazole and praziquantel in schoolchildren with schistosomiasis and geohelminths.

A double-blind placebo-controlled study of the concurrent administration of albendazole and praziquantel was conducted in>1500 children with high prevalences of geohelminths and schistosomiasis. The study sites were in China and the Philippines, including 2 strains of Schistosoma japonicum, and 2 different regions of Kenya, 1 each with endemic Schistosoma mansoni or Schistosoma haematobium. Neither medication affected the cure rate of the other. There was no difference between the side effect rate from albendazole or the double placebo. Praziquantel-treated children had more nausea, abdominal pain, and headache but these side effects were statistically more common in children with schistosomiasis, suggesting a strong influence of dying parasites. The subjects were followed for 6 months for changes in infection status, growth parameters, hemoglobin, and schistosomiasis morbidity. In all 4 sites, a significant 6-month increase in serum hemoglobin was observed in children who received praziquantel, strongly supporting population-based mass treatment.

Identification of the Schistosoma japonicum 22.6-kDa antigen as a major target of the human IgE response: similarity of IgE-binding epitopes to allergen peptides.

Human resistance to reinfection with Schistosoma mansoni and Schistosoma haematobium correlates with elevated IgE titers against worm antigens (soluble worm antigen preparation, SWAP). In S. mansoni infection, low levels of reinfection following chemotherapy are associated with the recognition of a cloned tegumental protein Sm22.6. Because of potential species-specific differences in resistance to schistosomes, we attempted to identify Schistosoma japonicum antigens recognized by human IgE. Following a survey of 176 infected individuals in Leyte, Philippines, we show that IgE antibodies from the majority of older, high-IgE/SWAP responders recognize antigens in the 22 (Sj22)-, 45-, 78- and 97-kDa range in SWAP. Limited IgE cross-reactivity between Sj22 and Sm22 was observed following a comparison of Filipino IgE responses to these antigens. The antigen was cloned from an adult S. japonicum lambda-ZAP cDNA library (Mindoro strain) by immunoscreening with pooled high-titer IgE antisera and a rabbit anti-Sj22 polyclonal antibody. The deduced amino acid sequence of the identified cDNA clone, MJ-1, showed significant homology to Sm22.6 (74%) and Sj22.6 (99%). Although the molecular sequence of Sj22.6 has already been reported, this is the first demonstration of its recognition by human IgE, thereby strengthening its potential as a vaccine candidate. Using an overlapping peptide approach, four IgE-binding epitopes were identified in Sj22.6, two of which exhibited similarities to known IgE-binding epitopes from codfish (Gad c 1) and beta-lactoglobulin-related allergens. These findings suggest that allergy and protective immunity to helminth infection may be linked by the structural similarities of epitopes recognized by human IgE.

Kuru and mad cow disease: understanding the prion theory.

A preponderance of evidence indicates that several neurodegenerative disorders are caused by prions: abnormally folded proteins that can induce abnormal folding in other normal protein molecules. Further, these "infections" can cross some species barriers.

The influence of sex and age on antibody isotype responses to Schistosoma mansoni and Schistosoma japonicum in human populations in Kenya and the Philippines.

We have investigated the effects of host age and sex on human antibody isotype responses to Schistosoma mansoni and Schistosoma japonicum adult worm (AW) and soluble egg (SEA) antigens, using sera from subjects in Kenya and the Philippines. Similar trends with age were observed between the two populations despite host, parasite and environmental differences between the two geographical locations. IgE to AW increased with age, whereas most isotype responses to SEA decreased with age. IgG1, IgG3 and IgG4 subclass responses to adult worm, however, did not show a broadly rising or falling pattern with age. Males were found to have higher IgG1, IgG4 and IgE to AW in both populations. This sex difference remained significant in the Kenyan population even after controlling statistically for confounding factors such as age and differences in intensity of infection. Analysis of S. mansoni and S. japonicum adult worm antigens reactive with IgE revealed a predominant 22 kDa band in both parasites. Only those individuals with relatively high IgE titres specifically reactive with S. mansoni or S. japonicum AW had detectable IgE against Sj22 or Sm22.

Identification and molecular cloning of a 67-kilodalton protein in Schistosoma japonicum homologous to a family of actin-binding proteins.

A monoclonal antibody to Schistosoma japonicum which conferred significant protection against cercarial challenge in mice was produced. The predicted translation product of the cDNA corresponding to the antigen recognized by this antibody was homologous to a newly identified family of actin-binding proteins. The expressed protein bound polymerized actin and was recognized by serum from patients infected with S. japonicum.

Immunity and morbidity in schistosomiasis japonicum infection.

Schistosomiasis japonica differs significantly from Schistosoma mansoni infection in several epidemiologic, immunologic, and operational characteristics for control. Because of numerous nonhuman hosts, transmission remains high despite aggressive case finding and treatment of human cases. Diagnosis of infection using the Kato-Katz stool technique is less sensitive and specific in this than in other species of human schistosomes, making case finding and treatment a less effective approach to control. Clinically, morbidity induced by S. japonicum appears unrelated to intensity of infection, and is more severe than that of S. mansoni in terms of liver pathology and stunting of child growth and development. Both hepatic enlargement and fibrosis appear to be reversible and preventable with aggressive treatment but several operational characteristics for control of infection due to S. japonicum make the community impact of case-finding and treatment with praziquantel less pronounced than would have been predicted by the analysis of individual cases. In the Philippines, rebound morbidity following reinfection mandates short treatment intervals between screening and treatment to have a significant impact on morbidity, while in China inapparent infection (infection not diagnosed by a single stool examination) appears to be a common cause for persistent hepatic pathology. The authors conclude that for S. japonicum, mass treatment or targeted mass treatment is a more cost-effective approach than case-finding and treatment for control.

Function and expression of a human idiotypic network in Schistosomiasis japonica.

The cross-reactive idiotype (Hu-SJ-CRIM) is defined by polyclonal human anti-idiotypic antibodies derived from chronically S. japonicum infected patients. The present study shows that serum levels of Hu-SJ-CRIM expressed by antibodies to S. japonicum soluble egg antigen (SEA) are associated with acute infection and hepatosplenic disease. Xenogeneic anti-idiotypic antisera (anti-Hu-SJ-CRIM) suppressed human lymphocyte blastogenesis to SEA in vitro by 47-82% (P < 0.05). These anti-idiotypic antibodies also suppressed in vitro granuloma formation induced by SEA coated heads in a dose dependent manner. This immunosuppression was antigen specific in that mitogen (PHA) or non-related antigen (PPD) induced blastogenic responses were not suppressed. Surprisingly, anti-idiotypic antibodies (anti-SJ-CRIM), which describe the mouse correlate CRIM were not suppressive in the human blastogenesis or in vitro granuloma formation assays. These data indicate a dichotomy in the function and specificity of the idiotype/anti-idiotype human and murine immune networks in S. japonicum infection. Thus, only the patient derived molecules and serology form the basis for an immunoregulatory network in Schistosomiasis japonica.

Schistosomiasis japonica in the Philippines: the long-term impact of population-based chemotherapy on infection, transmission, and morbidity.

The long-term impact of annual case-finding and chemotherapy with praziquantel on schistosomiasis japonica was examined in an 8-year longitudinal study in the Philippines. The prevalence, incidence, and intensity of infection and schistosome-induced hepatomegaly significantly decreased within 3-4 years of treatment and then stabilized despite continual population-based chemotherapy. Hepatomegaly rapidly developed in acutely infected persons, with 82% of subjects developing hepatic enlargement within 2 years of reinfection. These data suggest that abrupt discontinuation of current control measures in the Philippines may result in a rapid rebound in morbidity. Age-dependent acquired resistance to reinfection also developed in subjects chronically exposed to schistosomiasis japonica, suggesting that a vaccine may represent an alternative approach for control of this parasitic infection.

Schistosomiasis japonica and childhood nutritional status in northeastern Leyte, the Philippines: a randomized trial of praziquantel versus placebo.

The hypothesis that infection with Schistosoma japonicum causes decreased nutritional status was studied in a randomized trial among 170 males and females, mean (SD) age 11.4 (3.5) years, residing in an endemic region of northeastern Leyte, Philippines. The S. japonicum-infected children were randomized to receive praziquantel or placebo and followed-up six months after randomization. Stature, weight, triceps, subscapular, and calf skinfold thicknesses and their sum, and hemoglobin level were measured at baseline and follow-up. Schistosoma japonicum eggs were detected in Kato-Katz stool smears and the intensity of infection was assessed by quantitative egg count. Intensities of hookworm, ascaris, and trichuris infections were also measured. The six-month levels of the anthropometric measures and hemoglobin were adjusted for age and their baseline levels and then compared between the praziquantel and placebo groups. Treatment interactions were also analyzed by sex. Baseline anthropometric and hemoglobin levels and parasite infection intensities were the same in the two groups. At six months, the praziquantel group had significantly higher hemoglobin levels (P < 0.001) and sum of skinfolds (P < 0.001) than the placebo group. Males had a significantly greater increase in hemoglobin levels with treatment than did females. The hemoglobin increase was not due to changes in hookworm intensity. The results show that schistosomiasis japonica caused decreased nutritional status in children and probably is partly responsible for the malnutrition and reduction in growth for age described in prior cross-sectional studies.

Paramyosin: a candidate vaccine antigen against Schistosoma japonicum.

Paramyosin, a 97 kDa myofibrillar protein, is a candidate vaccine antigen for prevention of infection with the human parasite Schistosoma mansoni. To determine if paramyosin would also induce protection against Schistosoma japonicum, paramyosin was biochemically purified from S. japonicum adult worms. SDS-PAGE demonstrated a single protein with a molecular weight of 97 kDa. In four separate experiments, vaccination of mice with S. japonicum paramyosin without adjuvant induced significant resistance (62%-86%, P < 0.001) against cercarial challenge as compared to controls. These data suggest that S. japonicum paramyosin may represent a candidate vaccine for immunization against schistosomiasis japonica.

Impact of annual screening and chemotherapy with praziquantel on schistosomiasis japonica on Jishan Island, People's Republic of China.

The impact of annual screening and treatment with praziquantel on schistosomiasis japonica was examined on Jishan Island in Po Yang Lake, Jiangxi Province. China. Prevalence of infection in the community decreased from 39% in year 1 to 33% in year 3 with a corresponding decrease in the geometric mean egg count from 51 eggs per gram of stool (epg) to 31 epg. The most dramatic changes in infection status and intensity of infection were observed in younger individuals (0-19 years of age). The prevalence of hepatosplenomegaly also significantly decreased, again primarily in younger individuals. No change in the community prevalence of schistosome-induced hepatic fibrosis was observed as determined by ultrasonography. Longitudinal cohort analysis, however, demonstrated significant improvement in treated individuals with advanced hepatic fibrosis. These data indicate that annual screening and treatment had a significant impact on infection status and morbidity and suggest that community therapy may be an effective approach to control schistosomiasis japonica in lake regions and marshlands in China. Further studies are necessary to determine the optimal and most cost-effective approach for drug delivery.

Human monoclonal antibodies heterogeneously express a human cross-reactive idiotype associated with immune function in Schistosoma japonicum infection.

Hybridomas secreting human monoclonal antibodies (hMAb) were derived from Epstein Barr Virus (EBV) transformed lymphocytes of a patient with acute Schistosoma japonicum infection. Three IgG1 hMAb SJ-D, SJ-E, and SJ-F bind soluble egg antigens (SEA) as determined by ELISA. These hMAb exhibit identical western blot profiles, recognizing an epitope(s) of multiple antigens with apparent molecular weights between 42 and 75 kDa. Serological analysis of these hMAb revealed a heterogeneity in their expression of a specific human S. japonicum anti-SEA associated cross reactive idiotype designated Hu SJ-CRIM. The differential expression of idiotypy by these hMAb correlates with immunosuppression of blastogenesis of lymphocytes from schistosomiasis patients. The level of suppression mediated by hMAb expressing high levels of Hu SJ-CRIM ranged from 41% to 52% (p < 0.05) for antigen and 36% to 43% for mitogen. In contrast, hMAb SJ-D which expressed over two fold lower levels Hu SR-CRIM, on a per weight basis showed no suppressive immune function. The data show the heterogeneous expression of human idiotype associated with S. japonicum infection and the correlation of idiotype expression with immune function.

Schistosomiasis japonica on Jishan Island, Jiangxi Province, People's Republic of China: persistence of hepatic fibrosis after reduction of the prevalence of infection with age.

Hepatic fibrosis due to schistosomiasis japonica was examined by ultrasonography in a cross-sectional community study of 825 individuals on Jishan Island, Jiangxi Province, China. The prevalence of active infection was 39.4% with peak infection in the 10-19.9 years age group followed by a significant decline. A similar pattern was observed for intensity of infection. The prevalence of hepatomegaly in the midsternal line > or = 6 cm peaked at 60% in the fourth decade and remained elevated. A progressive increase in the severity of hepatic periportal fibrosis was observed with age, with advanced fibrosis peaking in the fifth decade. The proportion of individuals with advanced fibrosis was significantly greater in males than in females despite equivalent prevalence and intensity of schistosome infection. In addition, a positive association (P < 0.01) was found between periportal fibrosis and both hepatomegaly > or = 6 cm and splenomegaly. This study suggests that the natural history of schistosomiasis japonica in this hyperendemic community in China is marked by persistence of hepatomegaly and schistosome-induced periportal fibrosis in adults despite a decrease in the prevalence of infection.

Child growth, nutritional status, and schistosomiasis japonica in Jiangxi, People's Republic of China.

The association between schistosomiasis japonica and nutritional status and child growth was studied cross-sectionally in 239 males and females (age range 4-19.9 years) residing in Jishan Island in Po Yang Lake in an endemic region of Jiangxi, China. The presence of Schistosoma japonicum eggs in Kato stool smears and the intensity of schistosomiasis as assessed by quantitative egg count were determined, as were the presence of hookworm, Ascaris, and Trichuris eggs. Anthropometric measures included stature, weight, weight-for-height, upper arm muscle area, and the sum of triceps and subscapular skinfold thickness. The association between schistosomiasis and nutritional status and growth was analyzed with multivariable models adjusted for the influence of age, age2, and polyparasitism. The prevalence of schistosomiasis was approximately 70% in both males and females. Current schistosomiasis and its intensity were significantly related to reduced stature, weight, weight-for-height, and the sum of skinfolds (all P < 0.01) in females across the entire age-span. The greatest age-specific differences were during adolescence in females: 4 cm in height and 5 kg in weight. In males, intensity of schistosomiasis was related (P < 0.03) only to the sum of skinfolds. The cross-sectional associations between anthropometric reductions and schistosomiasis japonica in childhood and adolescence indicate a strong independent effect of infection on malnutrition and growth in this population from a highly endemic region of China.

Human EBV-transformed lymphocytes of patients with Schistosoma japonicum infection secrete idiotypically related immunoregulatory antibodies.

Lymphocytes derived from the peripheral blood of individuals infected with Schistosoma japonica were transformed in vitro with Ebstein-Barr virus (EBV). Serological characterization of antibody molecules revealed both antigen reactive (idiotypic) and anti-idiotypic transformants. One idiotypic EBV transformant, LO2C2, describes a major cross-reactive idiotype associated with anti-antigen binding molecules. Other antibody populations expressing idiotypic cross-reactivity were derived from separate individuals showing shared idiotypy in S. japonicum field study populations in the Republic of Philippines. Both idiotypic and anti-idiotypic molecules suppressed parasite antigen-driven blastogenesis of heterologous human peripheral blood lymphocytes. The data show a serologically related immunoregulatory immune network in patients in the Republic of the Philippines which is serologically distinct from idiotypy expressed in other selected S. japonicum endemic areas in the Far East.

Inhibition of phosphoinositide turnover by praziquantel in Schistosoma mansoni.

The effect of praziquantel on phosphoinositide turnover was examined in Schistosoma mansoni to determine if this anthelminthic modulates signal transduction pathways in parasites. Adult worms were radiolabeled with [3H]myoinositol for 24 hr and total inositol phosphate levels determined in the presence of praziquantel. Praziquantel inhibited inositol phosphate turnover when activated with NaF plus AlCl3 or with the nonhydrolyzable guanine nucleotide-binding protein analogue GTP gamma S. Furthermore, praziquantel decreased basal turnover of inositol phosphates. Inhibition was seen in both male and female worms as well as in schistosomula. These data indicate that inhibition of phosphoinositide turnover may contribute to the effect of praziquantel on parasite survival within the definitive host.

Child growth and schistosomiasis japonica in northeastern Leyte, the Philippines: cross-sectional results.

The association between schistosomiasis japonica and child growth was studied cross-sectionally in 1,561 males and females aged 4-19.9 years residing in an endemic region of northeastern Leyte, The Philippines. Stature, weight, upper arm muscle area, and sum of triceps and subscapular skinfold thicknesses were measured and related to presence of Schistosoma japonicum eggs in Kato stool smears and to the intensity of infection assessed by quantitative egg count. The presence of hookworm, ascaris, and trichuris eggs was also measured. Multivariable models were used to control for the effects of age, age2, and polyparasitism on growth. The prevalence of schistosomiasis was 31% in males and 22% in females, with the maximum prevalence in adolescence. In 8-19-year-old subjects, the intensity of schistosomiasis japonica was significantly related in males to reduced arm muscle area and sum of skinfolds (both P less than 0.01) and in females to reduced stature, weight, arm muscle area, and sum of skinfolds (all P less than 0.01). The greatest age-specific differences were during adolescence in both males and females. The growth retarding effects of intensity of schistosomiasis japonica were independent of the influence of other parasites, notably hookworm. Due to the magnitude of the schistosomiasis-associated growth differences in adolescence, adult body size, function and productivity may be affected.

Developmental expression of protein kinase C activity in Schistosoma mansoni.

The multicellular parasite Schistosoma mansoni undergoes complex physiologic changes during development from infective cercariae to adult worms in the mammalian host. The present study examined changes in protein kinase C (PKC) activity in S. mansoni during parasite maturation. Activation of PKC required Ca+2, phosphatidylserine, and either diacylglycerol or phorbol ester similar to mammalian PKC enzyme. A nine-fold increase in total PKC activity was found in adult worms as compared with larval parasites. Transformation of infective cercariae to parasitic schistosomula was associated with translocation of PKC activity from the cytosolic to membrane fraction. Tegumental extracts demonstrated significant PKC activity, suggesting a signal transduction system in the surface of the parasite. These data indicate that PKC activity is differentially expressed during parasite development and may have critical roles in regulation of cellular events in S. mansoni.