Genotypes and phenotypes of G6PD deficiency among Indonesian females across diagnostic thresholds of G6PD activity guiding safe primaquine therapy of latent malaria

Background Plasmodium vivax occurs as a latent infection of liver and a patent infection of red blood cells. Radical cure requires both blood schizontocidal and hypnozoitocidal chemotherapies. The hypnozoitocidal therapies available are primaquine and tafenoquine, 8-aminoquinoline drugs that can provoke threatening acute hemolytic anemia in patients having an X-linked G6PD-deficiency. Heterozygous females may screen as G6PD-normal prior to radical cure and go on to experience hemolytic crisis. Methods & findings This study examined G6PD phenotypes in 1928 female subjects living in malarious Sumba Island in eastern Indonesia to ascertain the prevalence of females vulnerable to diagnostic misclassification as G6PD-normal. All 367 (19%) females having <80% G6PD normal activity were genotyped. Among those, 103 (28%) were G6PD wild type, 251 (68·4%) were heterozygous, three (0·8%) were compound heterozygotes, and ten (2·7%) were homozygous deficient. The variants Vanua Lava, Viangchan, Coimbra, Chatham, and Kaiping occurred among them. Below the 70% of normal G6PD activity threshold, just 18 (8%) were G6PD-normal and 214 (92%) were G6PD-deficient. Among the 31 females with <30% G6PD normal activity were all ten homozygotes, all three compound heterozygotes, and just 18 were heterozygotes (7% of those). Conclusions In this population, most G6PD heterozygosity in females occurred between 30% and 70% of normal (69·3%; 183/264). The prevalence of females at risk of G6PD misclassification as normal by qualitative screening was 9·5% (183/1928). Qualitative G6PD screening prior to 8-aminoquinoline therapies against P. vivax may leave one in ten females at risk of hemolytic crisis, which may be remedied by point-of-care quantitative tests.

New evidence for tamoxifen as an antischistosomal agent: in vitro, in vivo and target fishing studies

Background: Praziquantel is the only drug available to treat schistosomiasis, and there is an urgent demand for new anthelmintic agents. Methodology & results: We conducted in-depth in vitro and in vivo studies and report a target fishing investigation. In vitro, tamoxifen was active against adult and immature worms at low concentrations (<5 μM). Tamoxifen at a single dose (400 mg/kg) or once daily for five consecutive days (100 mg/kg/day) in mice harboring either adult (patent infection) or juvenile (prepatent infection) significantly reduced worm burden (30–70%) and egg production (70–90%). Target fishing studies revealed propionyl-CoA carboxylase as a potential target for tamoxifen in Schistosoma mansoni and glucose uptake by S. mansoni was also significantly reduced. Conclusion: Our results provide news evidence of antiparasitic effect of tamoxifen and reveal propionyl-CoA carboxylase as a potential target.

TRYPANOSOMA VIVAX IN NIGERIAN GOATS: EFFECT OF CHEMOTHERAPY OF SERUM CONSTITUENTS OF RED SOKOTO BUCKS

The effect of trypanosome infection on serum protein and electrolyte levels was studied in Red Sokoto goats inoculated with Trypanosoma vivax and treated, during the course of the infection, with Berenil (diminazene aceturate), Samorin (isometamidium chloride) and Novidiurh (homidium chloride). During the infection total protein, albumin and albumin/globulin (A/G) ratio decreased significantly (P<0.05) while the globulin fraction and calcium increased progressively. Chloride concentration was elevated by the third week post infection and, despite treat met, by the sixth week. Untreated animals died within five to six weeks of patent infection showing terminal hypoproteinemia of 23.6% Treatment abolished trypanosomaemia within 48 hours and reversed the effect of the infection by the second or third week post drug administration. There were slight but insignificant differences in the levels of the parameters monitored in the different drug-treated groups However, four weeks post treatment pre infection levels of total protein and albumin, were not achieved by Berenil nor was therapy associated with modulation of the calcium and chloride concentrations to pre infection levels

Efficacy of a novel topical combination of esafoxolaner, eprinomectin and praziquantel in cats against Toxocara cati and Dipylidium caninum

NexGard® Combo, a novel topical antiparasitic product for cats, combines the insecticide/acaricide esafoxolaner with the nematocide eprinomectin and cestodicide praziquantel. The efficacy of this combination product was evaluated against two common endoparasites of global occurrence in cats, the nematode Toxocara cati and the cestode Dipylidium caninum, in five controlled studies using naturally or experimentally infected cats with parasites of North American, South African or European origin. Cats evaluated in these studies harbored patent infection of the target parasite confirmed through a pre-treatment fecal examination. In each study, cats were allocated randomly to two groups of equal size (8 or 10 cats per group per study), one group treated with a placebo (mineral oil) and the other with NexGard® Combo. Both treatments were administered once as a spot-on at 0.12 mL per kg body weight to deliver the minimum label dosage (1.44 mg/kg esafoxolaner, 0.48 mg/kg eprinomectin, and 10.0 mg/kg praziquantel) to the NexGard® Combo-treated cats. To determine efficacy, geometric mean parasite counts seven to 12 days after treatment of placebo-treated (control) cats and NexGard® Combo-treated cats were compared. The efficacy of NexGard® Combo was 98.8% and 100% against adult T. cati in two studies; and 98.0%, 98.3% and 93.2% against D. caninum in three studies. No adverse events related to treatment were observed throughout the studies. These studies demonstrate high efficacy against these major feline endoparasites and excellent acceptability of the novel topical antiparasitic combination of esafoxolaner, eprinomectin and praziquantel.

Collagenofibrotic glomerulopathy in a young cat

Collagenofibrotic glomerulopathy, also named collagen III glomerulopathy, is a rare glomerulopathy type caused by deposition of collagen III in the glomerular mesangium and subendothelial space. The aetiology of this entity is unknown and the pathological mechanism remains poorly understood. It is mostly seen in humans in Asian countries, especially in Japan. Collagenofibrotic glomerulopathy has been described in a macaque, in dogs, pigs and in a cat, published as renal glomerular fibrosis. Here, the authors present a case of collagenofibrotic glomerulopathy in a young European domestic shorthair cat, which developed a severe hypoproteinaemia, hypoalbuminaemia and proteinuria and showed a concurrent natural non-patent infection with the canid lungworm Angiostrongylus vasorum.

The Experimental Infections of the Human Isolate of Strongyloides Stercoralis in a Rodent Model (The Mongolian Gerbil, Meriones Unguiculatus)

Strongyloidiasis is life-threatening disease which is mainly caused by Strongyloides stercoralis infection. Autoinfection of the parasite results in long-lasting infection and fatal conditions, hyperinfection and dissemination (primarily in immunosuppressed hosts). However, mechanisms of autoinfection and biology remain largely unknown. Rodent models including mice and rats are not susceptible to the human isolate of S. stercoralis. Variations in susceptibility of the human isolate of S. stercoralis are found in dogs. S. ratti and S. venezuelensis infections in rats are an alternative model without the ability to cause autoinfection. The absence of appropriate model for the human isolate of strongyloidiasis hampers a better understanding of human strongyloidiasis. We demonstrated the maintenance of the human isolate of the S. stercoralis life cycle in the Mongolian gerbil (Meriones unguiculatus). The human isolate of S. stercoralis caused a patent infection in immunosuppressed gerbils, more than 18 months. The mean number of recovery adult parasitic worms were 120 ± 23 (1.2% of the initial dose) and L1s were 12,500 ± 7,500 after day 28 post-inoculation (p.i.). The prepatent period was 9–14 days. Mild diarrhoea was found in gerbils carrying a high number of adult parasitic worms. Our findings provided a promising model for studying biology and searching new alternative drugs against the parasites. Further studies about the hyperinfection and dissemination would be performed.

Controlled Human Hookworm Infection: Accelerating Human Hookworm Vaccine Development

Background Controlled human hookworm infection (CHHI) is a central component of a proposed hookworm vaccination-challenge model (HVCM) to test the efficacy of candidate vaccines. Critical to CHHI is the manufacture of Necator americanus infective larvae (NaL3) according to current Good Manufacturing Practice (cGMP) and the determination of an inoculum of NaL3 that is safe and reliably induces patent infection. Methods cGMP-grade NaL3 were produced for a phase 1 trial in 20 healthy, hookworm-naïve adults in the United States, who received either 25 or 50 NaL3. Participants were monitored for 12–18 weeks postinfection for safety, tolerability, and patency of N. americanus infection. Results Both NaL3 doses were well tolerated. Early manifestations of infection included pruritus, pain, and papulovesicular rash at the application site. Gastrointestinal symptoms and eosinophilia appeared after week 4 postinfection. The 50 NaL3 inoculum induced patent N. americanus infection in 90% of this dose group. Conclusions The inoculum of 50 NaL3 was well tolerated and consistently induced patent N. americanus infection suitable for future HVCM trials. Clinical Trials Registration NCT01940757.

Immunization and challenge shown by hamsters infected withOpisthorchis viverrinifollowing exposure to gamma-irradiated metacercariae of this carcinogenic liver fluke

Here we report findings to optimize and standardize conditions to attenuate metacercariae ofOpisthorchis viverriniby ionizing radiation to elicit protective immune responses to challenge infection. Metacercariae were gamma-irradiated and the ability of irradiated metacercariae to prevent patent infection of challenge metacercariae in hamsters was determined, as well as their ability to induce a host antibody response. Metacercariae irradiated in a dose-dependent manner, with 3, 5, 10, 12, 20, 25 and 50 Gray, were used to infect Syrian golden hamsters by stomach gavage to ascertain the effect of irradiation on ability of the worms to establish infection. In addition, other hamsters were infected with metacercariae irradiated with 20–50 Gray, followed by challenge with intact/wild-type (non-irradiated) metacercariae to determine the protective effect as established by the numbers of adult flukes, eggs ofO. viverriniin hamster faeces and anti-O. viverriniantibody titres. Significantly fewer worms were recovered from hamsters immunized with metacercariae irradiated at 20, 25 and 50 Gray than from control hamsters infected with intact metacercariae or 0 Gray, and the worms showed damaged reproductive organs. Faecal egg numbers were decreased significantly in hamsters immunized with 25 and 50 Gray metacercariae ofO. viverrini. Moreover, hamsters administered metacercariae that were protected elicited a robust, specific anti-fluke immunoglobulin G response compared to control hamsters, suggesting a role for antibody in protection elicited by radiation-attenuated metacercariae.