Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance.

Schistosomiasis, a major neglected tropical disease, affects more than 250 million people worldwide. Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. PZQ is the drug of choice for the treatment of schistosomiasis; it is effective against all major forms of schistosomiasis, although it is less active against juvenile than mature parasites. A pyrazino-isoquinoline derivative, PZQ is not considered to be toxic and generally causes few or transient, mild side effects. Increasingly, mass drug administration targeting populations in sub-Saharan Africa where schistosomiasis is endemic has led to the appearance of reduced efficacy of PZQ, which portends the selection of drug-resistant forms of these pathogens. The synthesis of improved derivatives of PZQ is attracting attention, e.g., in the (i) synthesis of drug analogues, (ii) rational design of pharmacophores, and (iii) discovery of new compounds from large-scale screening programs. This article reviews reports from the 1970s to the present on the metabolism and mechanism of action of PZQ and its derivatives against schistosomes.

First description of food-borne Salmonella enterica resistance regions R1 and R3 associated with IS26 elements.

In this study, we assessed the presence of IS26 in food-borne ASSuT-type Salmonella enterica isolates. A new genetic region (R3) was described, that included a C14 caspase gene between IS26 elements. R3 was present in two Salmonella Rissen isolates from a swine carcass and a meat handler, collected at the same abattoir. Furthermore, a new rearrangement of resistance region R1, harboring the blaTEM-1 gene flanked by IS26 elements, was identified in Salmonella Typhimurium and Salmonella 4,[5],12:i:-, from different samples. This study highlights the zoonotic potential of Salmonella spp. isolates and the possible role of IS26 in the mobilization of resistance genes.

Schistosome and liver fluke derived catechol-estrogens and helminth associated cancers.

Infection with helminth parasites remains a persistent public health problem in developing countries. Three of these pathogens, the liver flukes Clonorchis sinensis, Opisthorchis viverrini and the blood fluke Schistosoma haematobium, are of particular concern due to their classification as Group 1 carcinogens: infection with these worms is carcinogenic. Using liquid chromatography-mass spectrometry (LC-MS/MS) approaches, we identified steroid hormone like (e.g., oxysterol-like, catechol estrogen quinone-like, etc.) metabolites and related DNA-adducts, apparently of parasite origin, in developmental stages including eggs of S. haematobium, in urine of people with urogenital schistosomiasis, and in the adult stage of O. viverrini. Since these kinds of sterol derivatives are metabolized to active quinones that can modify DNA, which in other contexts can lead to breast and other cancers, helminth parasite associated sterols might induce tumor-like phenotypes in the target cells susceptible to helminth parasite associated cancers, i.e., urothelial cells of the bladder in the case of urogenital schistosomiasis and the bile duct epithelia or cholangiocytes, in the case of O. viverrini and C. sinensis. Indeed we postulate that helminth induced cancers originate from parasite estrogen-host epithelial/urothelial cell chromosomal DNA adducts, and here we review recent findings that support this conjecture.

Urothelial dysplasia and inflammation induced by Schistosoma haematobium total antigen instillation in mice normal urothelium.

OBJECTIVES: Squamous cell carcinoma of the urinary bladder has been associated with Schistosoma haematobium infection in many parts of Africa. The epidemiologic association is based on case control studies and on the close correlation of urinary bladder cancer incidence with prevalence of S. haematobium infection within different geographic areas. A parasite-tumor linkage is further suggested by the predominance of squamous cell (as opposed to transitional cell) morphology of bladder carcinomas seen in S. haematobium-endemic areas. The cellular mechanisms linking S. haematobium infection with cancer formation are not yet defined. In the present study, we hypothesized that the parasite antigens might induce alterations in urothelium. MATERIALS AND METHODS: We investigated the effects of S. haematobium total antigen in CD-1 mice normal bladders after intravesical administration of the parasite antigens. The bladders were analyzed histopathologically 20 and 40 weeks after treatment. RESULTS: Intravesical instillation of S. haematobium total antigens induces the development of urothelial dysplasia and inflammation. CONCLUSIONS: In our work, we demonstrate for the first time that S. haematobium antigens are the direct cause of alterations in urothelium.

Occurrence of Cryptosporidium parvum and Giardia duodenalis in healthy adult domestic ruminants.

To determine the prevalence and intensity of infection of Cryptosporidium spp. and Giardia duodenalis in healthy adult domestic ruminants, faecal samples were collected from 379 cattle of between 3 and 13 years old, 446 sheep and 116 goats selected at random from 60 dairy farms and 38 and 20 herds, respectively, in Galicia (NW Spain). Cryptosporidium spp. oocysts were detected in 32 cows (8.4%), 24 sheep (5.3%) and in nine goats (7.7%) from, respectively, 48.3% of the farms and 34.2 and 30.0% of the herds. The intensity of infection in cows ranged between 25 and 5,924 oocysts per gram of faeces (OPG), whereas in sheep and goats, the number of oocysts shed ranged from 8-515 OPG and from 17-782 OPG, respectively. Parasitization by Cryptosporidium spp. was significantly higher (P<0.05) in cows than in sheep and goats. G. duodenalis cysts were identified in 101 cows (26.6%), 86 sheep (19.2%) and 23 goats (19.8%) from, respectively, 96.6% of the farms and 92.1 and 90% of the herds. The number of cysts shed by cows ranged between 15 and 3,042 cyst per gram of faeces (CPG), whereas the intensity of infection in sheep and goats ranged from 16-3010 CPG and from 15-1845 CPG, respectively, and was significantly lower (P<0.05) than in cows and sheep. The number of Cryptosporidium spp. oocysts isolated from sheep and goats was insufficient for successful polymerase chain reaction analysis. Nevertheless, gene sequence analysis of the hsp70 and 18SrRNA genes of Cryptosporidium revealed the presence of only C. parvum in faecal samples from cows. Genotyping studies of the beta-giardin and glutamate dehydrogenase genes of G. duodenalis revealed mainly assemblage E of Giardia in cows, sheep and goat faecal samples. Assemblage B of G. duodenalis was also detected in one sheep sample. These animals should be considered as a possible source of cryptosporidiosis and giardiosis, thereby maintaining the infections on farms and in herds.

Diagnosis of first case of Balamuthia amoebic encephalitis in Portugal by immunofluorescence and PCR.

We report here the first Portuguese case of acute fatal granulomatous encephalitis attributed to Balamuthia mandrillaris, initially thought to be a brain tumor, which had a progressive and fatal outcome. Balamuthia mandrillaris is a free-living amoeba recognized as an uncommon agent of granulomatous encephalitis. Infections have been identified in immunocompromised hosts and in immunocompetent pediatric patients. Balamuthia infections are very rare, with only two reported cases in Europe. The case presented here occurred in a previously healthy boy who died 5 weeks after the onset of the symptoms. No evidence of immunological deficiency was noted, and testing for human immunodeficiency virus antibodies was negative. The symptoms were initially thought to be the result of a tumor, but histopathologic examination showed evidence of amoebic infection. Immunofluorescence staining of brain tissue identified B. mandrillaris as the infectious agent. The diagnosis was confirmed with PCR by detecting Balamuthia DNA in formalin-fixed brain tissue sections. Despite initiation of empirical antimicrobial therapy for balamuthiasis, the patient died 3 weeks after being admitted to the hospital. No source of infection was readily apparent.