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A pleomorphic neoplasm (PN) is described from sections of Onchocerca volvulus worms in nodules excised from Cameroonian patients. PN is confined to older, non-fecund, female worms, and those classed as moribund/dead. It is mainly composed of small, roundish, basophilic cells of diverse sizes, often forming a 'rosette' pattern around amorphous eosinophilic centres. The cells have a high nuclear/cytoplasmic ratio and up to 2-3 mitoses/high-power field; some become grossly enlarged, highly polymorphic and contain large, irregular blocks of chromatin. The eukaryotic PN cells first appear posteriorly in the pseudocoelom, probably from ovarian cells; they spread anteriorly, invading or compressing the uteri. Ivermectin treatment increased the prevalence PN from 3.7% of 1422 female worms in 637 patients before treatment to 17.5% of 1134 worms in 511 patients after 3 years treatment. Ivermectin at 400-800 microg/kg annually, or at 150 microg/kg or 400-800 microg/kg 3-monthly, over 3 years, did not increase the PN prevalence significantly, as compared with standard doses of 150 microg/kg annually. In other small series of African patients, PN prevalence increased in worms 2, 4, 6 and 10 months after ivermectin treatment; but there was no increase after treatment with amocarzine, albendazole or diethylcarbamazine and suramin. PN may partly account for the increased macrofilaricidal action of ivermectin on female O. volvulus in patients treated for 3 years at 3-monthly intervals.
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Parasitic helminths cause debilitating diseases that affect millions of people in primarily low-resource settings. Efforts to eliminate onchocerciasis and lymphatic filariasis in Central Africa through mass drug administration have been suspended because of ivermectin-associated serious adverse events, including death, in patients infected with the filarial parasite Loa loa. To safely administer ivermectin for onchocerciasis or lymphatic filariasis in regions co-endemic with L. loa, a strategy termed "test and (not) treat" has been proposed whereby those with high levels of L. loa microfilariae (>30,000/ml) that put them at risk for life-threatening serious adverse events are identified and excluded from mass drug administration. To enable this, we developed a mobile phone-based video microscope that automatically quantifies L. loa microfilariae in whole blood loaded directly into a small glass capillary from a fingerprick without the need for conventional sample preparation or staining. This point-of-care device automatically captures and analyzes videos of microfilarial motion in whole blood using motorized sample scanning and onboard motion detection, minimizing input from health care workers and providing a quantification of microfilariae per milliliter of whole blood in under 2 min. To validate performance and usability of the mobile phone microscope, we tested 33 potentially Loa-infected patients in Cameroon and confirmed that automated counts correlated with manual thick smear counts (94% specificity; 100% sensitivity). Use of this technology to exclude patients from ivermectin-based treatment at the point of care in Loa-endemic regions would allow resumption/expansion of mass drug administration programs for onchocerciasis and lymphatic filariasis in Central Africa.
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Lymphocele is a well-known complication of renal transplantation. Presenting symptoms are nonspecific; most patients are entirely asymptomatic. Herein, we have reported a case of lymphocele due to an asymptomatic lymphatic Wuchereria bancrofti filariasis with deterioration of graft function. A 53-year-old man with end-stage renal disease secondary to vascular disease was admitted 40 days after transplantation with vague, isolated abdominal pain. An abdomen and pelvis ultrasound examination demonstrated a cystic structure in the renal hilus. Graft function deteriorated, so the patient underwent puncture of the lymphocele followed by povidone iodine sclerotherapy. In the percutaneous drainage, we noted a fine whitish strand 4-mm thick similar to the shape of the stent, a part of which seemed to go into the transplantation fossa. Parasitological examination showed an adult female worm of W bancrofti measuring 6 cm. The test for microfilaremia was negative. The patient was treated for 10 days with a combination of Ivermectin and Albendazole associated with Doxycycline. The collection rapidly decreased after worm treatment. This case describes a post-renal transplantation lymphocele due to asymptomatic lymphatic filariasis.
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A comet assay was used to analyze DNA damage kinetics in Chinese hamster ovary (CHO-K1) cells induced by antiparasitic ivermectin (IVM) and the IVM-containing technical formulation Ivomec® (IVO; 1% IVM). Cells were treated with 50 µg ml(-1) IVM and IVO for 80 min, washed and re-incubated in antiparasiticide-free medium for 0-24 h until assayed using the single-cell gel electrophoresis assay (SCGE). Cell viability remained unchanged up to 3 h of incubation. After 6 h of treatment, cell survival decreased up to 75% and 79% in IVM- and IVO-treated cultures, respectively, remaining unchanged within 12-24 h after treatment. For both anthelmintics, biphasic behavior in DNA damage occurred during the incubation time. A time-dependent increase of IVM- and IVO-induced DNA damage was observed within 0 to 3 h after pulse treatment, revealed by a progressive decrease of undamaged cells and an increase in slightly damaged and damaged cells. Finally, a time-dependent decrease in IVM- and IVO-induced DNA damage was revealed by a progressive decrease of slightly damaged cells and the absence of damaged cells simultaneously with an increase in the frequency of undamaged cells during the final 18 h of incubation. Flow cytometry analysis revealed that both compounds are able to induce a marked increase in early and late apoptosis. Based on our observations, we could conclude that the decrease in DNA lesions is mostly related to IVM-induced cytotoxicity rather than attributable to a repair process.
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The development of moxidectin resistance (MOX-R) in sheep parasitic gastrointestinal nematodes already carrying multiple resistances to other anthelmintic groups has made control of these strains very difficult. The anthelmintic resistance patterns of MOX-R strains of Trichostrongylus colubriformis and Haemonchus contortus were characterized to provide an insight into the remaining role of anthelmintics in the control of such strains. Homozygous MOX-R individuals of both genera were unaffected by moxidectin. For MOX-R heterozygotes a dose rate of 200 microg/kg abamectin (ABA) given orally removed 25% of H. contortus while 200 microg/kg MOX given orally achieved a 72% reduction. Doubling the dose rate of ABA improved the mean efficacy to 37%. Consequently, in H. contortus, the degree of dominance differs markedly between the two anthelmintics. A dose rate of 8 mg/kg levamisole and 185 mg/kg napthalophos achieved >95% reduction in worm count of the MOX-R homozygous H. contortus but only 85 and 7%, respectively against the MOX-R homozygous T. colubriformis.
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Seven foals naturally infected with Strongyloides westeri were injected intramuscularly with ivermectin at a dosage rate of 200 mcg per kg body weight. No adverse effects to treatment were observed. Weekly faecal egg counts showed a greater than 99 per cent reduction of S. westeri egg output compared with 7 untreated foals during the 21 days following treatment.
For decades, onchocerciasis (or river blindness) was one of the most common infectious causes of blindness in the world. Primarily an infection of Africa, with limited distribution in the new world, disease due to the nematode Onchocerca volvulus is rapidly diminishing as a result of large public health campaigns targeting at risk populations in Africa and the Americas. Existing and newly-developed treatment strategies offer the chance to eliminate onchocercal ocular morbidity in some parts of the world. This article reviews these treatment strategies, current clinical and epidemiologic aspects of onchocerciasis, and the next steps toward elimination.
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The efficacy of a high dose of ivermectin (1.0 mg per kg Eqvalan liquid drench) on encysted cyathostomes was tested in a controlled study using 12 adult ponies with naturally acquired cyathostome infections. Six treated ponies and six non-treated controls were held in separate stalls for a period of 5 weeks. Cyathostome burdens, which included lumenal larvae, adults and encysted larvae, were determined at necropsy. The viability of encysted larvae, based on morphologic integrity, was assessed by observation of mural transillumination and by the histologic appearance of 12 larvae per pony. Efficacy against adult cyathostomes was 99.9%. Lumenal cyathostome larval numbers were reduced by 87%. Numbers of encysted cyathostome larvae, identified by transillumination of the large intestine, were reduced by 35%. However, this reduction was not statistically significant (P > 0.05) and differences in viability of encysted larvae were not observed. The data strongly indicated that ivermectin has little demonstrable effect on encysted equine cyathostomes.
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The toxicity of a number of emamectin benzoate homologues and photodegradates to five species of Lepidoptera was investigated using diet and foliar bioassays. The emamectin benzoate homologues B1a and B1b were equally toxic in the diet and foliar assays to Spodoptera exigua (Hübner), Heliothis virescens (F.), Tricoplusia ni (Hübner), and Spodoptera frugiperda (J. E. Smith), within each of these species. Plutella xylostella (L.) was the most sensitive species to emamectin benzoate. The AB1a photodegradate of emamectin benzoate was as toxic as the parent compound in the diet assay. However, in the foliage assay AB1a was 4.4-fold less toxic to S. exigua than the parent compound. The MFB1a photodegradate of emamectin benzoate was as toxic as the parent compound to P. xylostella, and 3.1 to 6.2 times as toxic as the parent compound to the other species in the diet assay. The order of toxicity of the photodegradates were AB1a > MFB1a > FAB1a > 8,9-Z-MAB1a > PAB1a.
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A total of 302 people were examined in 3 villages in the Moyamba District, Sierra Leone of microfilaria (mf) and clinical signs of Wuchereria bancrofti infection. Mf rates were 34.5% and 31.8% for Bonganema, Old Mosongo and Pelewahun respectively. The average mf rate of those examined was 34.8%. Analysed by age and sex, the highest mf rates were observed in males of age >/=21 years (46 - 56%). The relative risk of infection was significantly lower (P<0.000) for 5-10 year olds than 11+ year old individuals. Clinical studies of 284 individuals of age >/=11 years showed that recurrent fever was the commonest clinical sign observed and the rate was 5.9%. For the ages >/=41 years, the recurrent fever was 10%. The average hydrocele and elephantiasis rates were 2.5% and 1.1% respectively. For the ages >/=41 years, the hydrocele and elephantiasis rates were 4% and 3% respectively, indicating that Filariasis is an important public health problem in the area. Annual mass treatment of the study area residents with ivermectin for onchocerciasis has begun. Ivermectin has been reported to be effective for control of lymphatic Filariasis. The displacement of the population due to the undeclared war in the area will certainly negate the effects of the mass treatment programme.
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The macrocyclic lactones (MLs) are probably the anti-parasitic agents most widely used in the treatment of food producing animals, poultry, aquaculture and crops. Ivermectin was the first macrocyclic lactone product to be licensed for use about 20 years ago. A number of alternative products such abamectin, doramectin, emamectin, eprinomectin, moxidectin, milbemycin and selamectin, have been marketed since. Because of the increase in the number of ML drugs, there has been a steady increase in the number of published analytical methods for determination of their residues. In this paper, the structure and properties of the different ML drugs available on the market are described. The occurrence and persistence of ML residues in food is discussed in relation to marker residues and current maximum residue limits (MRLs) as defined in the European Union (EU). Methodologies for determination of ML residues in biological matrices are described in terms of extraction and clean-up methods used for different matrices. Detection systems for determination of ML residues are discussed with a particular emphasis placed on new developments in screening technologies and liquid chromatography with fluorescence or mass spectrometry.
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The Global Program to Eliminate Lymphatic Filariasis has been implemented to reduce human microfilaremia to levels low enough to break the transmission of the disease by using single annual doses of albendazole in combination with diethylcarbamazine or ivermectin. Many veterinary helminth parasites have developed resistance against both albendazole and ivermectin. Resistance to albendazole in veterinary nematodes is known to be caused by either of two single amino acid substitutions from phenylalanine to tyrosine in parasite beta-tubulin at position 167 or 200. We have developed assays capable of detecting these single nucleotide polymorphisms (SNPs) in Wuchereria bancrofti, and have applied them to microfilaria obtained from patients in Ghana and Burkina Faso. One of the SNPs was found in worms from untreated populations in both locations. Worms from treated patients had significantly higher frequencies of these mutations. These findings indicate that a beta-tubulin allele associated with benzimidazole resistance is being selected in these populations.
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To determine the efficacy of a topical formulation of eprinomectin against natural infestations of first (L1)-stage, and second and third (L2/L3)-stage larvae of Hypoderma spp.
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In experimental trials on cattle, ivermectin given SC at 200 micrograms/kg had 95% or better efficacy against adult and immature GI and pulmonary nematodes, including inhibited fourth-stage larvae of Ostertagia ostertagi. Studies of efficacy against ectoparasites revealed nearly 100% efficacy against sucking lice, psoroptic and sarcoptic mange mites and cattle grubs. Safety trials revealed no adverse effects with the recommended dosage, including bulls and pregnant cows. A few grub-infested cattle died from acute esophagitis associated with a host-parasite reaction after ivermectin injection.
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We conducted a nodule prevalence survey in four onchocerciasis sentinel communities in Moyo and two in Kanungu districts of Uganda. Seven (33.3%) out of 21 excised "onchocercomas" (nodules) in Moyo District and excised onchocercomas from four of six persons in Kanungu District turned out to be cysts of Taenia solium. We concluded that the prediction of nodule prevalence for noninvasive rapid epidemiologic assessment (REA) to target areas for mass chemotherapy with ivermectin in the African Program for Onchocerciasis Control (APOC) supported areas may have been influenced by other pathologies. T. solium infection may be the main cause of "onchocerciasis-associated epileptic seizures" in many onchocerciasis endemic communities that have been causally linked to onchocerciasis. Lastly, widespread neurocysticercosis may be a concern in mass treatment programs that provide praziquantel (for managing schistosomiasis) or albendazole (for managing intestinal worms or lymphatic filariasis) because these drugs may kill cerebral cysticerci, resulting in severe adverse events.
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Methanol-water (4:1, v/v) crude extracts (50 mg mL(-1)) of 25 Jamaican medicinal plants were screened in vitro for anthelmintic activity using infective third-stage larvae of Strongyloides stercoralis. The most effective extract was further chemically scrutinized to isolate and identify the source of the bioactivity, and the efficacy of this compound was compared with ivermectin. Eosin exclusion (0.1 mg mL(-1)) served as the indicator of mortality in all bioassays. A crude extract of Eryngium foetidum (Apiaceae) was significantly (Probit Analysis, P<0.05) more potent than the other plant extracts, taking 18.9 h to kill 50% (LT50) of the larvae. Further, the petrol extract of E. foetidum was significantly more effective (Probit Analysis, P<0.05) at killing the larvae (LT50, 4.7 h) than either its methanol-water or dichloromethane extract. The latter two effected less than 1% larval mortality after 120 h. With bioassay-driven column chromatography of the petrol extract, trans-2-dodecenal (eryngial) was identified and chemically isolated as the main anthelmintic compound in E. foetidum. There was a significant difference between the 24 h LD50 values (mm) of trans-2-dodecenal (0.461) and ivermectin (2.251) but there was none between the 48 h LD50 values (mm): trans-2-dodecenal (0.411) and ivermectin (0.499) in vitro.
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Ninety-two males, infected with Onchocerca volvulus, from an area of on-going transmission in the forest zone of southern Ghana were treated with albendazole. 31 patients received 800 mg daily x 3, 31 received 1200 mg daily x 3 and 30 others received 800 mg daily x 7. Albendazole was given as a single daily dose with a fatty breakfast. Detailed systemic, ocular and laboratory examinations were performed pretreatment and at intervals over one year. Nodules were extirpated on days 30 and 60 and examined by histopathology. All the dose regimes were well tolerated but were neither microfilaricidal nor macrofilaricidal. The main effect was embryotoxicity affecting all intra-uterine stages. The most encouraging results were obtained in the 800 mg daily x 3 group in which a prolonged suppression of skin microfilarial counts occurred. Controlled studies in combination with ivermectin are recommended to determine whether an additive effect of the two drugs would result in permanent sterilisation of the adult worms.
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We searched Medline, Clinical Evidence and the Cochrane Library using MeSH terms and text words 'strongyloides OR strongyloidiasis'. For Australian studies we included text words '(parasite* OR parasitic OR helminth*) AND Australia*'. We examined references contained in retrieved studies or identified from direct contact with researchers. Studies consistent with our objective that described their methods were eligible for inclusion.
We evaluated the efficacy and safety of topical selamectin, a novel avermectin, in eliminating naturally acquired Syphacia muris infections in rats and S. obvelata infections in mice. S. muris-positive rats were assigned randomly to 4 groups: selamectin (0.6 mg/kg), selamectin (6.0 mg/kg), fenbendazole-medicated (150 ppm) chow, and untreated. S. obvelata-positive mice were allocated into 4 groups similar to those for rats. Animals not exposed to pinworm-contaminated bedding were designated as negative controls. Treatment success was assessed weekly by anal tape impressions and by necropsy examinations at the end of week 9. Evaluations of intestinal contents at necropsy revealed that, although safe, topical selamectin was 100% ineffective in eliminating Syphacia spp. infections in rats and mice. Treatment with fenbendazole-medicated chow resulted in negative anal tape impressions beginning at week 2 in rats and week 1 in mice. Negative anal tape impressions in fenbendazole-treated animals were confirmed by negative intestinal content evaluations. Of the 2 treatments evaluated, fenbendazole-medicated chow remains an effective and practical method to eliminate pinworm infections in mice and rats.
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Levamisole, morantel, fenbendazole, or ivermectin was administered at 2-week intervals from May 1 through Sept 14, 1985, to breeding ewes (20 ewes/drug) infected with various gastrointestinal nematodes. All ewes had fewer gastrointestinal nematode eggs per gram of feces (epg) after 2 treatments, compared with pretreatment epg counts. Ewes administered ivermectin continued to have a low mean epg (0 to 3) throughout the study. The mean epg counts of ewes treated with levamisole increased from 3 to 483 during the study. This increase was similar to that of ewes treated with morantel (7 to 485 epg). The mean epg count of fenbendazole-treated ewes increased from 4 to 192 during the study. By the end of the study, the mean epg counts when expressed as a percentage of the pretreatment epg counts were 4% (ivermectin), 249% (fenbendazole), 627% (levamisole), and 630% (morantel). With the exception of the ivermectin-treated ewes, the epg count increased almost linearly in the ewes after the 2nd anthelmintic treatment. These data indicate that the gastrointestinal nematodes (including Haemonchus contortus) may have developed more resistance to levamisole and morantel than to fenbendazole. On the basis of the epg counts, resistance to ivermectin did not develop during the 4.5-month treatment period. The percentage of ewes shedding eggs after 2, 4, and 6 anthelmintic treatments was lowest for ewes treated with ivermectin (20%) and was similar (40%) for ewes treated with 1 of the other 3 anthelmintics. At the conclusion of the study, most of the ewes (90%) were shedding at least a small number of eggs, regardless of the anthelmintic treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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Onchocerciasis is one of the leading causes of blindness in the developing world. An estimated 40 million people are afflicted with this parasitic disease. World Health Organization vector control programs have had considerable success in interrupting the parasite transmission cycle in selected savanna regions of West Africa, but chemotherapeutic agents suitable for massive treatment campaigns have not been available. Controlled clinical studies have indicated that a single oral dose of ivermectin is safer and more effective therapy for onchocerciasis than the the standard seven- to 10-day course of diethylcarbamazine, the current drug of choice, and that ivermectin causes a more prolonged reduction in dermal microfilarial density. Patients treated with ivermectin are unable to infect the blackfly vector as long as the dermal microfilarial density remains low; therefore, once- or twice-yearly administration of ivermectin in community-wide therapy programs, either alone or in combination with vector control measures, may successfully interrupt transmission of the parasite and eventually eliminate the disease.
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Lymphatic filariasis (LF) in rural southeastern Nigeria is transmitted mainly by Anopheles spp. mosquitoes. Potential coinfection with Loa loa in this area has prevented use of ivermectin in the mass drug administration (MDA) strategy for LF elimination because of potential severe adverse L. loa-related reactions. This study determined if long-lasting insecticidal net (LLIN) distribution programs for malaria would interrupt LF transmission in such areas, without need for MDA. Monthly entomologic monitoring was conducted in sentinel villages before and after LLIN distribution to all households and all age groups (full coverage) in two districts, and to pregnant women and children less than five years of age in the other two districts. No change in human LF microfilaremia prevalence was observed, but mosquito studies showed a statistically significant decrease in LF infection and infectivity with full-coverage LLIN distribution. We conclude that LF transmission can be halted in southeastern Nigeria by full-coverage LLIN distribution, without MDA.
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We have identified a syndrome induced by mercuric chloride in BN rats in which there is evidence of tissue injury in many organs, with some features in common with graft-versus-host disease. There is also necrotizing leucocytoclastic vasculitis affecting the gut, and the importance of this is enhanced by the description in the accompanying paper of autoantibodies similar to those found in human systemic vasculitis. Our observations strengthen the analogies between this model and human autoimmune disease.
The combined effect of the Lymphatic Filariasis Elimination Programme (LFEP) and the National Schistosomiasis and Soil-transmitted Helminthiasis Control Programme (NSSCP) on soil-transmitted helminthiasis (STH) was evaluated. In September 2004, before mass drug administration (MDA) with ivermectin and albendazole by the LFEP in October, the prevalence and intensity of STH were recorded in 228 pupils in one primary school. After 8 months, all available pupils were re-examined, and the prevalence of Ascaris lumbricoides, Trichuris trichiura and hookworm had decreased from 0.9 to 0.7% (P=0.84), from 4.8 to 0.7% (P=0.004) and from 45.6 to 11.9% (P<0.001), respectively. Overall, 81.2% of the schoolchildren stated that they were treated by the LFEP in October 2004. After the 8 months follow-up, pupils were treated with praziquantel and albendazole by the present project (substitute for the NSSCP). After another 4 months (at 12 months follow-up), the prevalence of hookworm infection was reduced to 4.8% (P=0.003), while the prevalence of T. trichiura was reduced to 0.3% (P=0.54) and the prevalence of A. lumbricoides remained unchanged. Mass co-administration of ivermectin and albendazole by the LFEP had a significant effect on STH, which was further amplified by treatment with praziquantel and albendazole 4 months later.
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Some type A gamma-aminobutyric acid (GABA(A)) receptor agonists are effective in protecting against the formation of stomach lesions induced by ethanol. Natural product abamectin, one of the existing GABA(A) receptor agonists, might protect against the development of gastric ulcers induced by ethanol. We investigated the protective effect of abamectin against the formation of gastric mucosal lesions induced by ethanol in rats. Abamectin (3 mg/kg, p.o.) was given to rats 1 h before administration of ethanol [4 ml of a 30% (volume/volume) solution]. Mucosal lipid peroxidation (LPO), nitric oxide (NO) levels, and ulcer index were measured 3 h after gastric surgery (vagotomy vs. sham vagotomy) in treated versus control subjects. Abamectin attenuated ethanol-induced gastric ulceration, decreased LPO regeneration, and increased NO production in the gastric mucosa of rats in the sham vagotomy group. However, this protective effect of abamectin against ethanol-induced gastric lesions was not observed in rats in the group that underwent vagotomy. These results support the suggestion that administration of abamectin ameliorated the ethanol-induced gastric mucosal injury through elevation of NO production. Activation of the vagus nerve may be involved in the abamectin-associated gastric protection against the effects of ethanol in rats.
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Mites of 3 genera-Myobia, Myocoptes, and Radfordia -continue to plague laboratory mouse facilities, even with use of stringent biosecurity measures. Mites often spread before diagnosis, predominantly because of detection difficulty. Current detection methods have suboptimal sensitivity, are time-consuming, and are costly. A sensitive serodiagnostic technique would facilitate detection and ease workload. We evaluated whether total IgE increases could serve as a serodiagnostic marker to identify mite infestations. Variables affecting total IgE levels including infestation duration, sex, age, mite species, soiled-bedding exposure, and ivermectin treatment were investigated in Swiss Webster mice. Strain- and pinworm-associated effects were examined by using C57BL/6 mice and Swiss Webster mice dually infested with Syphacia obvelata and Aspiculuris tetraptera, respectively. Mite infestations led to significant increases in IgE levels within 2 to 4 wk. Total IgE threshold levels and corresponding sensitivity and specificity values were determined along the continuum of a receiver-operating characteristic curve. A threshold of 81 ng/mL was chosen for Swiss Webster mice; values above this point should trigger screening by a secondary, more specific method. Sex-associated differences were not significant. Age, strain, and infecting parasite caused variability in IgE responses. Mice exposed to soiled bedding showed a delayed yet significant increase in total IgE. Treatment with ivermectin reduced total IgE levels within 2 wk. Our data suggest that increases in total IgE in Swiss Webster and C57BL/6 mice warrant investigation, especially because mite infestations can rapidly elevate total IgE levels. We propose that using total IgE levels routinely in serologic panels will enhance biosecurity.