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Steady-state kinetics of the schistosomal hypoxanthine-guanine phosphoribosyltransferase.

Schistosomiasis is a trematode infection of some 200 million people. The hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) of the major etiologic agent, Schistosoma mansoni, has been proposed as a potential target for antischistosomal chemotherapy [Dovey, H. F., McKerrow, J. H., & Wang, C. C. (1984) Mol. Biochem. Parasitol, 11, 157-167]. The steady-state kinetic mechanism for the schistosomal HGPRTase has been determined by including both hypoxanthine and guanine in the forward and reverse reactions under identical conditions. Double-reciprocal plots of initial velocity versus the concentration of one substrate, at a series of fixed concentrations of the other, give groups of intersecting straight lines indicating a sequential mechanism for the schistosomal HGPRTase-catalyzed reactions. In product inhibition studies, the results show that magnesium pyrophosphate (MgPPi) is a noncompetitive inhibitor with respect to dimagnesium phosphoribose pyrophosphate (Mg2PRPP), hypoxanthine, and guanine. Also, magnesium inosine monophosphate (MgIMP) and magnesium guanosine monophosphate (MgGMP) are noncompetitive inhibitors with respect to hypoxanthine or guanine, respectively, but are competitive inhibitors to Mg2PRPP. Furthermore, Mg2PRPP is a competitive inhibitor with respect to MgIMP and MgGMP but is a non-competitive inhibitor to MgPPi. The minimum kinetic model which fits the experimental data is an ordered bi-bi mechanism, where the substrates bind to the enzyme in a defined order (first Mg2PRPP followed by the purine bases), while products are released in sequence (first MgPPi followed by MgIMP or MgGMP).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Defence against the immune barrage: helminth survival strategies.

Parasites have generated a range of countermeasures against the host immune system which allows their survival long enough for reproduction to occur. Parasite subsistence is enhanced by evasion of the immune response utilizing mechanisms such as antigenic variation of exposed immunogenic proteins, shedding of surface proteins which are the target of an immune response, and protease production to neutralise specific anti-parasite immune components. Recent advances in the fields of immunology and parasitology have highlighted a range of mechanisms by which the parasite actively modulates the immune response to allow survival. Parasite factors can directly suppress the function of certain subsets of immune cells as well as stimulating other cell populations which have suppressive activity. Strategies such as the skewing of the type 1-type 2 cytokine profile to that of a less appropriate response, and the mimicry of host immune regulatory proteins are becoming more widely acknowledged as means by which helminths enhance their survival. An illustration of the extent by which parasites can exploit host immune components is emphasized by the use of host cytokines as parasite growth factors. This review will examine some of the strategies developed by helminths which enables them not only to survive in the host, but also to prosper.

Animals↗

Parasitic diarrhea in normal and malnourished children.

Diarrhea is only one of the many manifestations of intestinal parasites. Environmental influences are inescapable, regardless of an individual's state of health: in a highly endemic region, intestinal parasitic colonization is almost the rule. The clinical expression of the parasitoses, however, is largely determined by host defenses; and when they are weakened, parasitic diarrhea is frequent and severe. Protein-energy malnutrition is by far the most important cause of immune deficiency in developing countries. Diarrhea caused by Strongyloides or Giardia is common and severe in malnourished children, while well-nourished children remain healthy carriers. These parasites require specific treatment in the malnourished; and the well-nourished should have preventive treatment when they are to receive corticosteroids or immunosuppressive agents. Diarrhea caused by Cryptosporidium spp. may be severe in malnourished or immunodeficient children, and recovery is achieved only after renutrition or treatment of the immunodeficiency.

Antinematodal Agents↗

Eosinophilia and helminthic infections.

Among microbial agents, helminths are the most common cause of eosinophilia. An approach to the evaluation of a patient with eosinophilia is outlined, with particular emphasis on clues in the history, examination and routine laboratory data that can help with the diagnosis. Multiple helminthic infections have been associated with eosinophilia, and the characteristic modes of spread, clinical manifestations, diagnostic tests and therapeutic considerations of these infections are discussed.

Animals↗

The fine structure of Caenorhabditis elegans N-glycans.

We report the fine structure of a nearly contiguous series of N-glycans from the soil nematode Caenorhabditis elegans. Five major classes are revealed including high mannose, mammalian-type complex, hybrid, fuco-pausimannosidic (five mannose residues or fewer substituted with fucose), and phosphocholine oligosaccharides. The high mannose, complex, and hybrid N-glycan series show a high degree of conservation with the mammalian biosynthetic pathways. The fuco-pausimannosidic glycans contain a novel terminal fucose substitution of mannose. The phosphocholine oligosaccharides are high mannose type and are multiply substituted with phosphocholine. Although phosphocholine oligosaccharides are known immunomodulators in human nematode and trematode infections, C. elegans is unique as a non-parasitic nematode containing phosphocholine N-glycans. Therefore, studies in C. elegans should aid in the elucidation of the biosynthetic pathway(s) of this class of biomedically relevant compounds. Results presented here show that C. elegans has a functional orthologue for nearly every known enzyme found to be deficient in congenital disorders of glycosylation types I and II. This nematode is well characterized genetically and developmentally. Therefore, elucidation of its N-glycome, as shown in this report, may place it among the useful systems used to investigate human disorders of glycoconjugate synthesis such as the congenital disorders of glycosylation syndromes.

Animals↗

Fasciola antigens as vaccines against fascioliasis and schistosomiasis.

Fascioliasis is an important trematode infection of herbivores worldwide with increasing evidence of prevalence as a disease of humans. Vaccination studies with purified native and recombinant Fasciola antigens suggest that this approach to diminished morbidity and mortality and reduced transmission is a realistic goal. Among the major potential vaccine candidates are fatty acid binding protein (FABP), cysteine (cathepsin) proteases, haemoglobulin, leucine aminopeptidase, and a saposin-like protein. In the case of Fasciola hepatica FABP, cross-reaction and cross-protection against Schistosoma mansoni is an important feature. In addition to protective effects with significant worm burden reductions, some vaccine candidates also have anti-fecundity (smaller flukes), anti-pathology (less liver lesions), and anti-embryonation effects. Optimism is tempered by the fact that fascioliasis in humans is an orphan disease and in need of governmental and foundation support.

Animals↗

Occasional parasitic infections of man in Papua New Guinea and Irian Jaya (New Guinea).

Most parasites of man in New Guinea are cosmopolitan species, widely distributed and highly prevalent in the island. Reports of other parasite infections are reviewed. This impoverished fauna includes anthroponotic species normally occurring at low prevalences, e.g. Isospora belli, Dientamoeba fragilis, Trichomonas hominis and a few zoonotic forms with pigs as reservoir hosts, notably Balantidium coli and Entamoeba polecki. Other zoonoses are very few and extremely rare. This may be due to the reduced placental mammal fauna. The potential for the spread of Taenia solium infection is highlighted, as is the unique zoogeographical distribution of the Strongloides species resembling S. fuelleborni. Enterobius gregorii is recorded for the first time from Papua New Guinea.

Adolescent↗

Induced expression of CYP2A5 in inflamed trematode-infested mouse liver.

Trematode infections have long been associated with specific types of cancer. We investigated the ability of the liver fluke Fasciola hepatica to alter host enzymes in a manner that might provide insight into the phenomenon of biologically associated cancers. Our data demonstrate an increased activity of the CYP2A5 isozyme in male mouse liver infected with F.hepatica. Induction of this enzyme was further assessed immunohistochemically. The infection affected CYP2A5 distribution in hepatic tissue. Inflammation and proliferation in liver tissue were observed at the same time that CYP2A5 activity increased. This enzyme is known to participate in the metabolism of several carcinogens which are common contaminants in environments of developing countries where parasitic infections may be prevalent.

Animals↗

The effects of mating system and genetic variability on susceptibility to trematode parasites in a freshwater snail, Lymnaea stagnalis.

The amount and distribution of genetic variability in host populations can have significant effects on the outcome of host-parasite interactions. We studied the effect of mating system and genetic variability on susceptibility of Lymnaea stagnalis snails to trematode parasites. Mating system of snails from eight populations differing in the amount of genetic variability was manipulated, and self- and cross-fertilized offspring were exposed to naturally occurring trematode parasites in a controlled lake experiment. Susceptibility of snails varied between populations, but mating-system treatment did not have a significant effect. Heterozygosity of snails was negatively correlated with the probability of trematode infection, however, suggesting that parasitic diseases may pose a serious threat to populations lacking genetic variability.

Analysis of Variance↗

Diseases of cattle in the Solomon Islands.

Between 1967 and 1977 a study was made of diseases of cattle in the Solomon Islands. Tuberculosis was found in only 3 herds and was eradicated by 1975. Brucellosis serology revealed very few reactors and by 1977 the herds involved were considered free of the disease. Significant serological reactions were found to Leptospira interrogans serovars pomona, hardjo, autumnalis and jez-bratislava. There was evidence that infectious bovine rhinotracheitis and mucosal disease were present. Seventeen parasites were identified of which Haematobia irritans exigua, Haemonchus placei, Oesophagostomum radiatum and Ceylonocotyle streptocoelium were widely distributed. Nutritional stress occurred under some forms of husbandry but environmental stress was minimal. The Solomon Islands are therefore in a most favourable situation with regard to diseases of cattle.

Animals↗

Anthelmintics. Current concepts in the treatment of helminthic infections.

This article discusses the anthelmintics now in common use and describes their mode of action and toxic side effects. The drugs reviewed include: pyrantel pamoate, mebendazole, piperazine, thiabendazole, niclosamide, praziquantel, niridazole, oxamniquine and diethylcarbamazine. Most of the common roundworm intestinal infections respond to treatment with pyrantel pamoate, which has the advantage of single-dose therapy. Trichuriasis requires therapy with mebendazole, while the filariases are treated with diethylcarbamazine. There is no specific therapy for trichinellosis, but its symptoms can be alleviated. Intestinal cestode infections respond to treatment with niclosamide and cerebral cysticercosis to praziquantel, but echinococcal hydatid disease still requires surgical intervention in certain cases, although prolonged treatment with mebendazole shows promise. The greatest recent advance in the therapy of helminthiases is the development of praziquantel which effectively treats the most severe of these infections.

Anthelmintics↗

Efficacy of purified schistosoma japonicum egg antigens for ELISA serodiagnosis of human Schistosomiasis japonica: specificity and sensitivity.

At present, there is no consensus that purified schistosome egg antigens offer any advantage in the diagnosis of schistosomiasis by enzyme linked immunosorbent assay (ELISA). Previously, we demonstrated by multiple techniques that the major serologic antigens in Schistosoma japonicum soluble egg antigen (SEA) are glycoproteins, and that the glycoproteins with highest specificity and sensitivity are hydrophobes. We therefore tested these materials for their specificity, sensitivity and cost effectiveness in the ELISA. In this study we used five SEA fractions that varied in their purity and antigenicity. The order of immunologic specific activity in the ELISA, measured by titration of a standard sera pool, was: hydrophobic glycoproteins (highest), crude SEA glycoproteins, hydrophilic glycoproteins, crude SEA, and SEA proteins (lowest). Complexity (purity) of these materials were (in rank order), hydrophilic glycoproteins (purest), hydrophobic glycoproteins, crude glycoproteins, SEA proteins, and crude SEA (most complex). Epidemiologic sensitivity in the ELISA was tested on limited but well characterized populations. At high antigen coating concentration (0.5 microgram/well), the only antigen fraction with poor sensitivity was SEA proteins. There was little difference in epidemiologic sensitivity between the purer fractions with highest immunologic sensitivity (hydrophobic glycoproteins and crude SEA glycoproteins) and the crude SEA which possesses intermediate immunologic sensitivity. Differences in epidemiologic sensitivity were most pronounced when wells were coated at an antigen concentration (0.1 microgram/well) where crude SEA began to fail. Specificity for all preparations, assessed by reactivity with sera from patients with other trematode infections and with cestode and nematode infections, was excellent. The clinical sensitivity of the ELISA employing crude S. japonicum SEA is so high, and the specificity so good, that the increased immunologic sensitivity of partially purified antigens had little effect on epidemiologic sensitivity. This is not true for the S. mansoni ELISA where crude antigens had inferior sensitivity and specificity.

Antibodies↗