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Donor-derived strongyloidiasis infection in SOT recipients has high mortality. Effective donor screening and prophylaxis in high-risk SOT recipients may help to decrease morbidity and mortality associated with donor-derived strongyloidiasis.
Porcine reproductive and respiratory syndrome virus (PRRSV) is a devastating viral pathogen of swine that causes huge financial losses in the pig industry worldwide. Ivermectin is known to be a potent inhibitor of importin α/β-mediated nuclear transport and exhibits antiviral activity towards several RNA viruses by blocking the nuclear trafficking of viral proteins. Although PRRSV replication occurs exclusively in the cytoplasm of infected cells, the nucleocapsid (N) protein has been shown to distinctly localize in the nucleus and nucleolus throughout infection. Here, we sought to assess whether ivermectin suppresses PRRSV replication in cultured porcine alveolar macrophage (PAM) cells and to investigate the effect of ivermectin on the subcellular localization of the PRRSV N protein. Our data demonstrate that ivermectin treatment inhibits PRRSV infection in PAM-pCD163 cells in a dose-dependent manner. The antiviral activity of ivermectin on PRRSV replication was most effective when cells were treated during the early stage of infection. Treatment of PRRSV-infected cells with ivermectin significantly suppressed viral RNA synthesis, viral protein expression, and progeny virus production. However, immunofluorescence and cell fractionation assays revealed that ivermectin was incapable of disrupting the nuclear localization of the N protein, both in PRRSV-infected PAM-pCD163 cells and in PAM cells stably expressing the PRRSV N protein. This finding suggests that an alternative mechanism of action accounts for the ability of ivermectin to diminish PRRSV replication. Taken together, our results suggest that ivermectin is an invaluable therapeutic or preventative agent against PRRSV infection.
CLM significantly impaired the skin disease-associated life quality in child and adult patients living in urban slums in North Brazil. After treatment with ivermectin, life quality normalised rapidly.
Avermectin (AVM) and ivermectin (IVM) are potent pesticides and acaricides which have been widely used during the past 30 years. As insect resistance to AVM and IVM is greatly increasing, alternatives are urgently needed. Here, we report two novel AVM derivatives, tenvermectin A (TVM A) and TVM B, which are considered a potential new generation of agricultural and veterinary drugs. The molecules of the TVMs were designed based on structure and pharmacological property comparisons among AVM, IVM, and milbemycin (MBM). To produce TVMs, a genetically engineered strain, MHJ1011, was constructed from Streptomyces avermitilis G8-17, an AVM industrial strain. In MHJ1011, the native aveA1 gene was seamlessly replaced with milA1 from Streptomyces hygroscopicus. The total titer of the two TVMs produced by MHJ1011 reached 3,400 mg/liter. Insecticidal tests proved that TVM had enhanced activities against Tetranychus cinnabarinus and Bursaphelenchus xylophilus, as desired. This study provides a typical example of exploration for novel active compounds through a new method of polyketide synthase (PKS) reassembly for gene replacement. The results of the insecticidal tests may be of use in elucidating the structure-activity relationship of AVMs and MBMs.
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Hookworm-related cutaneous larva migrans (CLM) is a frequent cutaneous disease among travelers returning from the tropics. It can be misdiagnosed or treated incorrectly. We present a 42-year-old French patient who contracted the disease during a holiday in Thailand and who experienced an extensive CLM syndrome with a less frequent abdominal localization and a pseudo-multimetameric homolateral topography. The condition was late diagnosed and secondarily efficiently cured by a unique administration of ivermectin. Simple anamnestic information--often revealing beach activities--and clinical aspect of the creeping eruption allow to prevent diagnosis delay and to avoid aggressive or inadequate intervention.
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Avermectin and its analogues, produced by Streptomyces avermitilis, are major commercial antiparasitic agents in the field of animal health, agriculture, and human infections. They are 16-membered pentacyclic lactone compounds derived from polyketide and linked to a disaccharide of the methylated deoxysugar l-oleandrose. Labeling studies, analyses of the biosynthetically blocked mutants, and the identification of the avermectin gene cluster allows characterization of most of the biosynthetic pathway. Recent completion of S. avermitilis genome sequencing is also expected to help in revealing the precise biosynthetic sequence and the complicated regulatory mechanism for avermectin biosynthesis, which has been long-awaited to be elucidated. The well characterized avermectin biosynthetic pathway and availability of S. avermitilis genome information in combination with the recent development of combinatorial biosynthesis should allow us to redesign more potent avermectin analogues and to engineer S. avermitilis as a more efficient host for the production of important commercial analogues.
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Detailed epidemiological mapping of three isolated foci of hyperendemic blinding onchocerciasis was undertaken in three West African countries as part of community trials of ivermectin, a new microfilaricide for the treatment of human onchocerciasis. The results show that the geographical distribution of the prevalence and intensity of onchocerciasis infection in the community can be very different from what was expected on the basis of demographic and entomological information. The technique of detailed epidemiological mapping is an important tool for the identification of target populations for large scale ivermectin treatment of onchocerciasis. It is being used extensively in the Onchocerciasis Control Programme in West Africa.
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We randomly allocated 657 patients who had onchocerciasis to 150 microg/kg ivermectin yearly (reference group), 150 microg/kg every 3 months, 400 then 800 microg/kg yearly, or 400 then 800 microg/kg every 3 months. We took skin snip samples from every patient before, and 3 years and 4 years after the first dose, and, at the same time excised one subcutaneous O volvulus nodule, which was examined histologically. The primary outcome was the vital status of the female worms. Analysis was done per protocol.
An economic decision tree model terminating in Markov processes was developed to estimate the cost and health impacts of four interventions on an annual cohort of 27,700 U.S.-bound Asian refugees: 1) "No Program," 2) U.S. "Domestic Screening and Treatment," 3) "Overseas Albendazole and Ivermectin" presumptive treatment, and 4) "Overseas Albendazole and Domestic Screening for Strongyloides". Markov transition state models were used to estimate long-term effects of parasitic infections. Health outcome measures (four parasites) included outpatient cases, hospitalizations, deaths, life years, and quality-adjusted life years (QALYs).
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The microfilaricidal drug, ivermectin, is used by the Onchocerciasis Control Program for mass treatment in West Africa's savanna zones. To avoid reinfestation of these protected savanna areas, ivermectin treatment has been proposed in selected forest zones of the Ivory Coast with high microfilarial loads. A pilot project was carried out in a small stream catchment area with extremely high onchocerciasis transmission. With the exception of children under 5 years of age, pregnant women, and those who were ill, the entire population of this area (n = 1553) was treated orally with ivermectin (200 mcg/kg of body weight). The prevalence rate of microfilariae dropped from 60.1% before treatment to 33.2% at 6 months after treatment. The community microfilarial load was reduced from 29.7 to 5.6 microfilariae/skin strip. Thus, the level of endemicity changed from hyper- to hypoendemic as a result of treatment. In order to maintain hypoendemicity, regular ivermectin treatment of all newcomers to the study area is recommended.
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With the implementation of programs to control lymphatic filariasis and soil-transmitted helminths using broad spectrum anthelmintics, including albendazole and ivermectin, there is a need to develop an in vitro assay for detection of drug resistance. This report describes an in vitro assay for measuring the effects of ivermectin and benzimidazoles on the motility of larvae of the hookworm species Ancylostoma ceylanicum, A. caninum, and Necator americanus, and Strongyloides species including Strongyloides stercoralis, and S. ratti. A dose-response relationship was demonstrated with each of the parasite species, with distinct differences observed between the various species. In pilot field testing of the assay with N. americanus larvae recovered from human fecal samples, a dose-response relationship was observed with ivermectin. While the assay has demonstrated the ability to determine drug responsiveness, its usefulness in resistance detection will require correlation with the clinical outcome among individuals infected with parasite strains showing different drug sensitivities.
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Based on resistance selection, the life tables of abameetin-resistant (AbR), fenpropathrin-resistant (FeR), and susceptible (S) strains of Tetranychus cinnabarinus at 15 degrees C, 20 degrees C, 25 C, 28 degrees C, 31 degrees C, 34 degrees C, and 36 degrees C were constructed, and the development duration, fertility, and intrinsic rate of increase (r(m)) of the strains were compared, aimed to understand the relative fitness of T. cinnabarinus resistant strains at different temperatures. The results indicated that compared with S strain, AbR and FeR strains had longer development duration at 15 degrees C but lower fertility at 20 degrees C-28 degrees C, and their relative fitness (represented by r(m)) was smaller at 15 degrees C but similar at 20 degrees C - 31 degrees C. For AbR and FeR strains, the fitness cost was moderate at 15 degrees C but lower at 20 degrees C - 31 degrees C. However, at high temperatures ( > or =34 degrees C), FeR strain possessed remarkable fitness cost while AbR strain showed better fitness.
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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.
Dorsal root ganglion (DRG) neurons respond to ATP with transient, persistent or biphasic inward currents. In contrast, the ATP responses in nodose neurons are persistent. These sustained currents are also heterogeneous, with one component being accounted for by P2X2/3 receptors, and the residual response probably mediated by P2X2 receptors, although the direct evidence for this has been lacking. In the present study, we examined the P2X receptors on DRG and nodose neurons from P2X3-deficient (P2X3-/-) mice, using whole cell voltage-clamp recording and immunohistochemistry. We found that all P2X3-/- DRG neurons lacked rapidly desensitizing response to ATP, and both DRG and nodose neurons from P2X3-null mutant mice no longer responded to alpha,beta-methylene ATP (alphabetameATP). In contrast, ATP evoked persistent inward current in 12% of DRG neurons and 84% of nodose neurons from P2X3-/- mice. This retained persistent response to ATP on nodose neurons had an EC50 for ATP of 77 microm, was antagonized by Cibacron blue and pyridoxal-5-phosphate-6-azophenyl-2',4'-disulphonic acid, potentiated by Zn2+ and acidification, but not enhanced by ivermectin or diinosine pentaphosphate. 2',3'-O-Trinitrophenyl-ATP antagonized this response with an IC50 of 8 microm. All these properties are consistent with those of recombinant P2X2 homomeric receptors. Furthermore, specific P2X2 receptor immunoreactivity detected in wild-type sensory neurons was unaltered in null mutant mice. Therefore, the alphabetameATP-insensitive persistent responses on nodose neurons are likely to be mediated by P2X2 homomers, which contribute to 60% of currents evoked by 100 microm ATP in the wild type.
BK Polyomavirus (BKPyV) is a ubiquitous nonenveloped human virus that can cause severe disease in immunocompromised populations. After internalization into renal proximal tubule epithelial cells, BKPyV traffics through the ER and enters the cytosol. However, it is unclear how the virus enters the nucleus. In this study, we elucidate a role for the nuclear localization signal located on the minor capsid proteins VP2 and VP3 during infection. Site-directed mutagenesis of a single lysine in the basic region of the C-terminus of the minor capsid proteins abrogated their nuclear localization, and the analogous genomic mutation reduced infectivity. Additionally, through use of the inhibitor ivermectin and knockdown of importin β1, we found that the importin α/β pathway is involved during infection. Overall these data are the first to show the significance of the NLS of the BKPyV minor capsid proteins during infection in a natural host cell.
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Collaborative efforts between the national onchocerciasis and LF programmes are critical as plans to scale interventions are moving forward and thus, alternative strategies needed in loiasis co-endemic areas which may include the new L. loa test and treat strategy using the Cellscope, or interventions such as integrated vector management, or anti Wolbachia therapy using doxycycline.
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A single, 10-minute, at-home application of ivermectin was more effective than vehicle control in eliminating head-louse infestations at 1, 7, and 14 days after treatment. (Funded by Topaz Pharmaceuticals [now Sanofi Pasteur]; ClinicalTrials.gov numbers, NCT01066585 and NCT01068158.).
The physiological effects of dihydroavermectin B1 on insect central neurones have been investigated using a culture system derived from the brains of embryonic cockroaches. In these neuronal cultures 60% of the cells respond to the application of gamma-aminobutyric acid (GABA) with a conductance increase; these responses are blocked by picrotoxin but not by bicuculline. Dihydroavermectin B1, a representative of a potentially new class of insecticide, also produces a slow conductance increase which is blocked by picrotoxin and inverted by the injection of chloride ions. Qualitatively similar responses are also evoked by dihydroavermectin B1 in some neurones unaffected by GABA and in neurones exposed to elevated Mg2+ concentrations to inhibit synaptic release mechanisms. In a subpopulation of neurones dihydroavermectin B1 evokes a transient, initial excitation prior to the apparent chloride conductance increase.
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These data demonstrate the effectiveness of three insecticidal compounds administered systemically to cattle for controlling the cattle-feeding mosquito An. arabiensis. Eprinomectin and fipronil provided the longest-lasting control. Such endectocidal treatments in cattle are a promising new strategy for control of residual, outdoor malaria transmission and could effectively augment current interventions which target more endophilic vector species.
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Resistance to ivermectin and related drugs is an increasing problem for parasite control. The mechanism of ivermectin resistance in nematode parasites is currently unknown. Some P-glycoproteins and multidrug resistance proteins have been found to act as membrane transporters which pump drugs from the cell. A disruption of the mdrla gene, which encodes a P-glycoprotein in mice, results in hypersensitivity to ivermectin. Genes encoding members of the P-glycoprotein family are known to exist in nematodes but the involvement of P-glycoprotein in nematode ivermectin-resistance has not been described. Our data suggest that a P-glycoprotein may play a role in ivermectin resistance in the sheep nematode parasite Haemonchus contortus. A full length P-glycoprotein cDNA from H. contortus has been cloned and sequenced. Analysis of the sequence showed 61-65% homology to other P-glycoprotein/multidrug resistant protein sequences, such as mice, human and Caenorhabditis elegans. Expression of P-glycoprotein mRNA was higher in ivermectin-selected than unselected strains of H. contortus. An alteration in the restriction pattern was also found for the genomic locus of P-glycoprotein derived from ivermectin-selected strains of H. contortus compared with unselected strains. P-glycoprotein gene structure and/or its transcription are altered in ivermectin-selected H. contortus. The multidrug resistance reversing agent, verapamil, increased the efficacy of ivermectin and moxidectin against a moxidectin-selected strain of this nematode in jirds (Meriones unguiculatus). These data indicate that a P-glycoprotein may be involved in resistance to ivermectin and other macrocyclic lactones in H. contortus.