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1.
Emerg Infect Dis ; 26(12): 1-9, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33219786

RESUMO

Domestic dogs are responsible for nearly all the ¼59,000 global human rabies deaths that occur annually. Numerous control measures have been successful at eliminating dog-mediated human rabies deaths in upper-income countries, including dog population management, parenteral dog vaccination programs, access to human rabies vaccines, and education programs for bite prevention and wound treatment. Implementing these techniques in resource-poor settings can be challenging; perhaps the greatest challenge is maintaining adequate herd immunity in free-roaming dog populations. Oral rabies vaccines have been a cornerstone in rabies virus elimination from wildlife populations; however, oral vaccines have never been effectively used to control dog-mediated rabies. Here, we convey the perspectives of the World Organisation for Animal Health Rabies Reference Laboratory Directors, the World Organisation for Animal Health expert committee on dog rabies control, and World Health Organization regarding the role of oral vaccines for dogs. We also issue recommendations for overcoming hesitations to expedited field use of appropriate oral vaccines.


Assuntos
Mordeduras e Picadas , Doenças do Cão , Vacina Antirrábica , Vírus da Raiva , Raiva , Animais , Doenças do Cão/prevenção & controle , Cães , Humanos , Raiva/prevenção & controle , Raiva/veterinária , Vírus da Raiva/imunologia
3.
Drug Metab Dispos ; 42(10): 1656-62, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25063672

RESUMO

The clinical development of fedratinib, a Janus kinase (JAK2) inhibitor, was terminated after reports of Wernicke's encephalopathy in myelofibrosis patients. Since Wernicke's encephalopathy is induced by thiamine deficiency, investigations were conducted to probe possible mechanisms through which fedratinib may lead to a thiamine-deficient state. In vitro studies indicate that fedratinib potently inhibits the carrier-mediated uptake and transcellular flux of thiamine in Caco-2 cells, suggesting that oral absorption of dietary thiamine is significantly compromised by fedratinib dosing. Transport studies with recombinant human thiamine transporters identified the individual human thiamine transporter (hTHTR2) that is inhibited by fedratinib. Inhibition of thiamine uptake appears unique to fedratinib and is not shared by marketed JAK inhibitors, and this observation is consistent with the known structure-activity relationship for the binding of thiamine to its transporters. The results from these studies provide a molecular basis for the development of Wernicke's encephalopathy upon fedratinib treatment and highlight the need to evaluate interactions of investigational drugs with nutrient transporters in addition to classic xenobiotic transporters.


Assuntos
Proteínas de Membrana Transportadoras/efeitos dos fármacos , Pirrolidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Deficiência de Tiamina/induzido quimicamente , Tiamina/metabolismo , Encefalopatia de Wernicke/etiologia , Encefalopatia de Wernicke/metabolismo , Animais , Transporte Biológico Ativo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos , Janus Quinase 2/antagonistas & inibidores , Masculino , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Pirrolidinas/sangue , Pirrolidinas/farmacocinética , Ratos , Sulfonamidas/sangue , Sulfonamidas/farmacocinética
4.
Can Commun Dis Rep ; 49(1): 1-4, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36815867

RESUMO

Importation of rabies-infected dogs results in significant and costly public and animal health risks. In January 2022, a dog in Ontario, Canada, which was imported from Iran in June 2021, developed rabies, leading to an extensive public health investigation and administration of rabies post-exposure prophylaxis to 37 individuals. The dog was infected with a rabies virus variant known to circulate in Iran. This is the second reported case of a rabies-infected dog imported into Canada in 2021 from a high-risk country for canine mediated rabies. This case emphasizes the need for public education regarding the risks associated with importing dogs from high-risk countries for canine-mediated rabies and the benefits of establishing a public health team specializing in rabies exposure investigations.

5.
J Am Vet Med Assoc ; 261(7): 1045-1053, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36884381

RESUMO

OBJECTIVE: To provide epidemiological information on the occurrence of animal and human rabies in the US during 2021 and summaries of 2021 rabies surveillance for Canada and Mexico. PROCEDURES: State and territorial public health departments and USDA Wildlife Services provided data on animals submitted for rabies testing in 2021. Data were analyzed temporally and geographically to assess trends in domestic animal and wildlife rabies cases. RESULTS: During 2021, 54 US jurisdictions reported 3,663 rabid animals, representing an 18.2% decrease from the 4,479 cases reported in 2020. Texas (n = 456 [12.4%]), Virginia (297 [8.1%]), Pennsylvania (287 [7.8%]), North Carolina (248 [6.8%]), New York (237 [6.5%]), California (220 [6.0%]), and New Jersey (201 [5.5%]) together accounted for > 50% of all animal rabies cases reported in 2021. Of the total reported rabid animals, 3,352 (91.5%) involved wildlife, with bats (n = 1,241 [33.9%]), raccoons (1,030 [28.1%]), skunks (691 [18.9%]), and foxes (314 [8.6%]) representing the primary hosts confirmed with rabies. Rabid cats (216 [5.9%]), cattle (40 [1.1%]), and dogs (36 [1.0%]) accounted for 94% of rabies cases involving domestic animals in 2021. Five human rabies deaths were reported in 2021. CLINICAL RELEVANCE: The number of animal rabies cases reported in the US decreased significantly during 2021; this is thought to be due to factors related to the COVID-19 pandemic.


Assuntos
COVID-19 , Doenças do Gato , Doenças dos Bovinos , Quirópteros , Doenças do Cão , Raiva , Animais , Gatos , Bovinos , Cães , Humanos , Animais Domésticos , Animais Selvagens , Doenças do Gato/epidemiologia , Doenças dos Bovinos/epidemiologia , COVID-19/epidemiologia , COVID-19/veterinária , Doenças do Cão/epidemiologia , Raposas , Mephitidae , New York , Pandemias , Vigilância da População , Raiva/epidemiologia , Raiva/veterinária , Guaxinins , Estados Unidos/epidemiologia
6.
Environ Toxicol Chem ; 41(10): 2375-2385, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35833595

RESUMO

Numerous per- and polyfluoroalkyl substances (PFAS) are of growing concern worldwide due to their ubiquitous presence, bioaccumulation and adverse effects. Surface waters in the United States have displayed elevated concentrations of PFAS, but so far discrete water sampling has been the commonly applied sampling approach. In the present study we field-tested a novel integrative passive sampler, a microporous polyethylene tube, and derived sampling rates (Rs ) for nine PFAS in surface waters. Three sampling campaigns were conducted, deploying polyethylene tube passive samplers in the effluent of two wastewater treatment plant (WWTP) effluents and across Narragansett Bay (Rhode Island, USA) for 1 month each in 2017 and 2018. Passive samplers exhibited linear uptake of PFAS in the WWTP effluents over 16-29 days, with in situ Rs for nine PFAS ranging from 10 ml day-1 (perfluoropentanoic acid) to 29 ml day-1 (perfluorooctanesulfonic acid). Similar sampling rates of 19 ± 4.8 ml day-1 were observed in estuarine field deployments. Applying these Rs values in a different WWTP effluent predicted dissolved PFAS concentrations mostly within 50% of their observations in daily composite water samples, except for perfluorobutanoic acid (where predictions from passive samplers were 3 times greater than measured values), perfluorononanoic acid (1.9 times), perfluorodecanoic acid (1.7 times), and perfluoropentanesulfonic acid (0.1 times). These results highlight the potential use of passive samplers as measurement and assessment tools of PFAS in dynamic aquatic environments. Environ Toxicol Chem 2022;41:2375-2385. © 2022 SETAC.


Assuntos
Fluorocarbonos , Poluentes Químicos da Água , Monitoramento Ambiental/métodos , Polietileno/análise , Água , Poluentes Químicos da Água/análise
7.
Environ Pollut ; 300: 118963, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35134426

RESUMO

The deployment of aqueous film forming foams (AFFF) used for firefighting during emergencies and training often releases per- and polyfluoroalkyl substances (PFAS) into the environment. In October 2018, first responders in Providence, RI, USA applied an AFFF during a fuel spill. Due to the proximity of the incident to the upper reaches of Narragansett Bay (NB), an unknown quantity of gasoline and AFFF entered the estuary via surface runoff and stormwater drains. Water samples near the spill were collected approximately 15 h after the incident and analyzed for 24 PFAS. Minor increases in measured PFAS concentrations were observed relative to pre- and post-spill samples at monitoring sites near the incident, except 6:2-fluorotelomer sulfonate (6:2-FTS) that peaked post-spill (max 311 ng/L). After performing the total oxidizable precursor (TOP) assay on water samples and the AFFF concentrate, significant increases in perfluorocarboxylic acids (PFCAs) were observed. One compound, 6:2 fluorotelomer mercaptoalkylamido sulfonate (6:2-FTSAS), was identified as a major component of the AFFF used. Peak areas of 6:2-FTSAS and the degradation product 6:2-FTSAS-sulfoxide corresponded to observed increases in the TOP assay results and were useful as tracers of AFFF in surrounding waters. Elevated levels of PFAS at the time of sampling were limited to a confined area of the Providence River due to river flow and tidal action. Observed concentrations were also compared to hydrodynamic model results, and results confirmed rapid dissipation of AFFF components with distance from the spill. However, modeled results did not capture possible secondary releases of AFFF from local municipal stormwater and sewer infrastructure, as observational data suggest. The multiple lines of evidence of PFAS present in surface waters permitted a better assessment of the potential environmental impacts from products such as AFFF for which the chemical composition is largely unknown.


Assuntos
Fluorocarbonos , Poluentes Químicos da Água , Estuários , Fluorocarbonos/análise , Rios , Água , Poluentes Químicos da Água/análise
8.
PLOS Glob Public Health ; 2(5): e0000357, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36962180

RESUMO

Domestic animals can serve as consequential conveyors of zoonotic pathogens across wildlife-human interfaces. Still, there has been little study on how different domestic species and their behaviors influence the zoonotic risk to humans. In this study, we examined patterns of bat encounters with domestic animals that resulted in submission for testing at the rabies laboratories of the Canadian Food Inspection Agency (CFIA) during 2014-2020. Our goals were specifically to examine how the number of bats submitted and the number of rabies positive bats varied by the type of domestic animal exposure and whether domestic cats were indoor or free-roaming. The CFIA reported 6258 bat submissions for rabies testing, of which 41.5% and 8.7% had encounter histories with cats and dogs, respectively. A much smaller fraction of bat submissions (0.3%) had exposure to other domestic animals, and 49.5% had no domestic animal exposure. For the bat submissions related to cats, and where lifestyle was noted, 91.1% were associated with free-roaming cats and 8.9% with indoor cats. Model results indicated the probability of a rabies-positive bat was the highest with a history of dog association (20.2%), followed by bats with no animal exposure (16.7%), free-roaming cats (6.9%), cats with unspecified histories (6.0%) and the lowest probability associated with non-free-roaming (indoor) cats (3.8%). Although there was lower rabies prevalence in bats associated with cats compared to dogs, the 4.8 fold higher number of cat-bat interactions cumulatively leads to a greater overall rabies exposure risk to humans from any free-roaming outdoor cats. This study suggests that free-roaming owned cats may have an underappreciated role in cryptic rabies exposures in humans and as a significant predator of bats. Preventing free-roaming in cats is a cost-effective and underutilized public health recommendation for rabies prevention that also synergistically reduces the health burden of other feline-associated zoonotic diseases and promotes feline welfare and wildlife conservation.

9.
J Am Vet Med Assoc ; 260(10): 1157-1165, 2022 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-35522584

RESUMO

OBJECTIVE: To provide epidemiological information on animal and human cases of rabies in the US during 2020 and summaries of 2020 rabies surveillance for Canada and Mexico. ANIMALS: All animals submitted for laboratory diagnosis of rabies in the US during 2020. PROCEDURES: State and territorial public health departments and USDA Wildlife Services provided 2020 rabies surveillance data. Data were analyzed temporally and geographically to assess trends in domestic and wildlife rabies cases. RESULTS: During 2020, 54 jurisdictions submitted 87,895 animal samples for rabies testing, of which 85,483 (97.3%) had a conclusive (positive or negative) test result. Of these, 4,479 (5.2%) tested positive for rabies, representing a 4.5% decrease from the 4,690 cases reported in 2019. Texas (n = 580 [12.9%]), Pennsylvania (371 [8.3%]), Virginia (351 [7.8%]), New York (346 [7.7%]), North Carolina (301 [6.7%]), New Jersey (257 [5.7%]), Maryland (256 [5.7%]), and California (248 [5.5%]) together accounted for > 60% of all animal rabies cases reported in 2020. Of the total reported rabid animals, 4,090 (91.3%) involved wildlife, with raccoons (n = 1,403 [31.3%]), bats (1,400 [31.3%]), skunks (846 [18.9%]), and foxes (338 [7.5%]) representing the primary hosts confirmed with rabies. Rabid cats (288 [6.4%]), cattle (43 [1.0%]), and dogs (37 [0.8%]) accounted for 95% of rabies cases involving domestic animals in 2020. No human rabies cases were reported in 2020. CONCLUSIONS AND CLINICAL RELEVANCE: For the first time since 2006, the number of samples submitted for rabies testing in the US was < 90,000; this is thought to be due to factors related to the COVID-19 pandemic, as similar decreases in sample submission were also reported by Canada and Mexico.


Assuntos
COVID-19 , Doenças do Gato , Doenças dos Bovinos , Quirópteros , Doenças do Cão , Raiva , Gatos , Cães , Animais , Estados Unidos , Bovinos , Humanos , Raiva/epidemiologia , Raiva/veterinária , Animais Domésticos , Pandemias , Doenças do Gato/epidemiologia , Doenças do Cão/epidemiologia , Doenças dos Bovinos/epidemiologia , Equidae , Vigilância da População , COVID-19/veterinária , Guaxinins , Mephitidae , Animais Selvagens , Raposas , New York
10.
Can Commun Dis Rep ; 48(6): 238-242, 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-37333573

RESUMO

In July 2021, a dog was imported into Canada from Iran and subsequently developed clinical signs of rabies within 11 days of arrival. Following laboratory confirmation of the diagnosis of rabies, local, provincial and federal inter-agency collaboration was required to complete contact tracing to identify all persons and domestic animals that may have been exposed to the rabid dog during the potential virus shedding period. This case highlights the risks of importing animals from known canine rabies-endemic areas, identifies gaps in current dog importation policies that pose potential risk to human and animal health and prompts ongoing vigilance for this deadly disease among human and animal health partners, as well as members of the public who adopt imported dogs.

11.
J Wildl Dis ; 58(1): 241-244, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34814183

RESUMO

The arctic fox variant of the rabies virus (RABV) is enzootic in the circumpolar north. Reports of abortive RABV exposures motivated a retrospective analysis of sera from 41 arctic foxes (Vulpes lagopus) captured at Karrak Lake in Nunavut, Canada, during 2011-15. Estimated RABV antibody prevalence among foxes was 15% (95% confidence interval, 7-28%).


Assuntos
Vírus da Raiva , Raiva , Animais , Regiões Árticas , Canadá/epidemiologia , Raposas , Nunavut/epidemiologia , Raiva/epidemiologia , Raiva/veterinária , Estudos Retrospectivos
12.
Zoonoses Public Health ; 68(6): 601-608, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33987941

RESUMO

Rabies occurs throughout the Arctic, representing an ongoing public health concern for residents of northern communities. The Arctic fox (Vulpes lagopus) is the main reservoir of the Arctic rabies virus variant, yet little is known about the epidemiology of Arctic rabies, such as the ecological mechanisms driving where and when epizootics in fox populations occur. In this study, we provide the first portrait of the spatio-temporal spread of rabies across northern Canada. We also explore the impact of seasonal and multiannual dynamics in Arctic fox populations and climatic factors on rabies transmission dynamics. We analysed data on rabies cases collected through passive surveillance systems in the Yukon, Northwest Territories, Nunavut, Nunavik and Labrador from 1953 to 2014. In addition, we analysed a large and unique database of trapped foxes tested for rabies in the Northwest Territories and Nunavut from 1974 to 1984 as part of active surveillance studies. Rabies cases occurred in all Arctic regions of Canada and were relatively synchronous among foxes and dogs (Canis familiaris). This study highlights the spread of Arctic rabies virus variant across northern Canada, with contrasting rabies dynamics between different yet connected areas. Population fluctuations of Arctic fox populations could drive rabies transmission dynamics in a complex way across northern Canada. Furthermore, this study suggests different impacts of climate and sea ice cover on the onset of rabies epizootics in northern Canada. These results lay the groundwork for the development of epidemiological models to better predict the spatio-temporal dynamics of rabies occurrence in both wild and domestic carnivores, leading to better estimates of human exposure and transmission risk.


Assuntos
Mudança Climática , Ecossistema , Raposas , Raiva/veterinária , Animais , Regiões Árticas/epidemiologia , Canadá/epidemiologia , Humanos , Vigilância da População , Raiva/epidemiologia
13.
J Am Vet Med Assoc ; 258(11): 1205-1220, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33978439

RESUMO

OBJECTIVE: To provide epidemiological information on animal and human cases of rabies occurring in the United States during 2019 and summaries of 2019 rabies surveillance for Canada and Mexico. ANIMALS: All animals submitted for laboratory diagnosis of rabies in the United States during 2019. PROCEDURES: State and territorial public health departments and USDA Wildlife Services provided data on animals submitted for rabies testing in the United States during 2019. Data were analyzed temporally and geographically to assess trends in domestic and wildlife rabies cases. RESULTS: During 2019, 53 jurisdictions submitted 97,523 animal samples for rabies testing, of which 94,770 (97.2%) had a conclusive (positive or negative) test result. Of these, 4,690 tested positive for rabies, representing a 5.3% decrease from the 4,951 cases reported in 2018. Texas (n = 565 [12.0%]), New York (391 [8.3%]), Virginia (385 [8.2%]), North Carolina (315 [6.7%]), California (276 [5.9%]), and Maryland (269 [5.7%]) together accounted for almost half of all animal rabies cases reported in 2019. Of the total reported rabid animals, 4,305 (91.8%) were wildlife, with raccoons (n = 1,545 [32.9%]), bats (1,387 [29.6%]), skunks (915 [19.5%]), and foxes (361 [7.7%]) as the primary species confirmed with rabies. Rabid cats (n = 245 [5.2%]) and dogs (66 [1.4%]) accounted for > 80% of rabies cases involving domestic animals in 2019. No human rabies cases were reported in 2019. CONCLUSIONS AND CLINICAL RELEVANCE: The overall number of animal rabies cases decreased from 2018 to 2019. Laboratory diagnosis of rabies in animals is critical to ensure that human rabies postexposure prophylaxis is administered judiciously.


Assuntos
Doenças do Gato , Quirópteros , Doenças do Cão , Raiva , Animais , Animais Domésticos , Animais Selvagens , Canadá , Gatos , Doenças do Cão/epidemiologia , Cães , México , New York , North Carolina , Vigilância da População , Raiva/epidemiologia , Raiva/prevenção & controle , Raiva/veterinária , Guaxinins , Texas , Estados Unidos/epidemiologia , Virginia
14.
PLoS Negl Trop Dis ; 14(3): e0008113, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32210439

RESUMO

Despite proactive measures to prevent raccoon rabies entering Canada from the United States, several incursions of this disease have occurred. The largest outbreak, first reported in December 2015 in the city of Hamilton, Ontario, has resulted in the reporting of 449 animal cases as of December 31, 2018. Initial phylogenetic studies on the index case suggested that this outbreak was not due to local cross-border spread from the Niagara region of the United States where raccoon rabies has persisted for several years. Phylogenetic analysis of whole genome sequences of a viral collection from the Hamilton area and several US states indicates that a long-distance translocation of a diseased animal from southeastern New York State was responsible for this incursion. The role of the skunk as a potential secondary host supporting persistence and / or spread of the virus is also examined.


Assuntos
Doenças dos Animais/epidemiologia , Doenças Transmissíveis Importadas/epidemiologia , Surtos de Doenças , Raiva/veterinária , Guaxinins , Doenças dos Animais/virologia , Animais , Doenças Transmissíveis Importadas/virologia , Genótipo , New York , Ontário/epidemiologia , Filogenia , Raiva/epidemiologia , Raiva/virologia , Vírus da Raiva/classificação , Vírus da Raiva/genética , Vírus da Raiva/isolamento & purificação , Sequenciamento Completo do Genoma
15.
J Assoc Med Microbiol Infect Dis Can ; 5(3): 201-208, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36341314

RESUMO

A 21-year-old, previously healthy male presented to hospital following 1 week of bilateral asymmetric ascending paralysis, odynophagia, and dysphagia. Initial magnetic resonance imaging (MRI) of the spine revealed an abnormal increased T2 signal with predominant dorsal column involvement and sparing of white matter throughout the cervical cord and extending to T5. The initial presumptive diagnosis was an acute infectious, versus inflammatory, myelitis. On reviewing the history, family members recalled a bat scratch on the left hand, sustained months prior, for which the patient did not seek or receive post-exposure prophylaxis (PEP). Rabies virus (RABV) RNA was detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in two saliva samples, while nuchal skin biopsy and cerebrospinal fluid (CSF) were negative. Serum was negative for RABV neutralizing antibody. Sequencing and phylogenetic analyses identified the infecting RABV as a variant associated with silver-haired bats. Following risk assessment of exposure, 67 health care workers and several family members were offered PEP.


Un homme de 21 ans auparavant en santé a consulté à l'hôpital parce qu'il souffrait de paralysie ascendante, asymétrique et bilatérale, d'odynophagie et de dysphagie depuis une semaine. Une première imagerie par résonance magnétique (IRM) du rachis a révélé une augmentation anormale du signal T2 avec atteinte prédominante de la colonne dorsale et épargne de la matière blanche dans toute la colonne cervicale jusqu'à la vertèbre T5. Le diagnostic provisoire en était un de myélite infectieuse, et non inflammatoire. À la prise de l'histoire, les membres de la famille se sont souvenus d'une égratignure de chauve-souris sur la main gauche du patient plusieurs mois auparavant, qui n'a pas été suivie d'une prophylaxie postexposition (PPE). Les chercheurs ont décelé l'ARN du virus de la rage (RABV) par amplification en chaîne par polymérase quantitative de transcription inverse (RT-qPCR) dans deux échantillons de salive, mais constaté un résultat négatif de la biopsie de la peau nucale et du liquide céphalorachidien. Le sérum était négatif à l'anticorps neutralisant du RABV. Les analyses de séquençage et de phylogénétique ont confirmé une contamination par une variante du RABV associée aux chauves-souris argentées. Après une évaluation du risque d'exposition, 67 travailleurs de la santé et plusieurs membres de la famille se sont fait offrir une PPE.

16.
Viruses ; 12(1)2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963517

RESUMO

Rabies in wildlife has been successfully controlled in parts of Europe and North America using oral rabies vaccination, i.e., the distribution of baits containing live-attenuated virus strains. Occasionally, these vaccines caused vaccine virus-induced rabies cases. To elucidate the mechanisms of genetic selection and the effect of viral populations on these rabies cases, a next generation sequencing approach as well as comprehensive data analyses of the genetic diversity of Street Alabama Dufferin (SAD) and ERA vaccine virus strains and vaccine-induced rabies cases from Canada and several European countries were conducted. As a result, twelve newly generated sets of sequencing data from Canada and Poland were added to a pool of previously investigated samples. While the population-based analysis showed a segregation of viruses of ERA vaccine-induced rabies cases from those of SAD Bern original (SAD Bernorig)-derived rabies cases, the in-depth variant analysis revealed three distinct combinations of selected variants for the ERA vaccine-induced cases, suggesting the presence of multiple replication-competent haplotypes in the investigated ERA-BHK21 vaccine. Our findings demonstrate the potential of a deep sequencing approach in combination with comprehensive analyses on the consensus, population, and variant level.


Assuntos
Variação Genética , Genoma Viral , Vacina Antirrábica/efeitos adversos , Vírus da Raiva/genética , Raiva/etiologia , Animais , Animais Selvagens/virologia , Encéfalo/patologia , Encéfalo/virologia , Canadá , Europa (Continente) , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , RNA Viral/genética , Vírus da Raiva/classificação , Seleção Genética
17.
PLoS One ; 15(4): e0231877, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315352

RESUMO

Alterations in fibroblast growth factor receptor (FGFR) genes have been identified as potential driver oncogenes. Pharmacological targeting of FGFRs may therefore provide therapeutic benefit to selected cancer patients, and proof-of-concept has been established in early clinical trials of FGFR inhibitors. Here, we present the molecular structure and preclinical characterization of INCB054828 (pemigatinib), a novel, selective inhibitor of FGFR 1, 2, and 3, currently in phase 2 clinical trials. INCB054828 pharmacokinetics and pharmacodynamics were investigated using cell lines and tumor models, and the antitumor effect of oral INCB054828 was investigated using xenograft tumor models with genetic alterations in FGFR1, 2, or 3. Enzymatic assays with recombinant human FGFR kinases showed potent inhibition of FGFR1, 2, and 3 by INCB054828 (half maximal inhibitory concentration [IC50] 0.4, 0.5, and 1.0 nM, respectively) with weaker activity against FGFR4 (IC50 30 nM). INCB054828 selectively inhibited growth of tumor cell lines with activation of FGFR signaling compared with cell lines lacking FGFR aberrations. The preclinical pharmacokinetic profile suggests target inhibition is achievable by INCB054828 in vivo with low oral doses. INCB054828 suppressed the growth of xenografted tumor models with FGFR1, 2, or 3 alterations as monotherapy, and the combination of INCB054828 with cisplatin provided significant benefit over either single agent, with an acceptable tolerability. The preclinical data presented for INCB054828, together with preliminary clinical observations, support continued investigation in patients with FGFR alterations, such as fusions and activating mutations.


Assuntos
Morfolinas/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Administração Oral , Animais , Linhagem Celular Tumoral , Feminino , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos SCID , Morfolinas/química , Morfolinas/farmacocinética , Neoplasias/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Pirróis/química , Pirróis/farmacocinética , Ratos , Ratos Nus , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Am Vet Med Assoc ; 256(2): 195-208, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31910075

RESUMO

OBJECTIVE: To describe rabies and rabies-related events occurring during 2018 in the United States. ANIMALS: All animals submitted for laboratory diagnosis of rabies in the United States during 2018. PROCEDURES: State and territorial public health departments provided data on animals submitted for rabies testing in 2018. Data were analyzed temporally and geographically to assess trends in domestic animal and wildlife rabies cases. RESULTS: During 2018, 54 jurisdictions reported 4,951 rabid animals to the CDC, representing an 11.2% increase from the 4,454 rabid animals reported in 2017. Texas (n = 695 [14.0%]), Virginia (382 [7.7%]), Pennsylvania (356 [7.2%]), North Carolina (332 [6.7%]), Colorado (328 [6.6%]), and New York (320 [6.5%]) together accounted for almost half of all rabid animals reported in 2018. Of the total reported rabies cases, 4,589 (92.7%) involved wildlife, with bats (n = 1,635 [33.0%]), raccoons (1,499 [30.3%]), skunks (1,004 [20.3%]), and foxes (357 [7.2%]) being the major species. Rabid cats (n = 241 [4.9%]) and dogs (63 [1.3%]) accounted for > 80% of rabid domestic animals reported in 2018. There was a 4.6% increase in the number of samples submitted for testing in 2018, compared with the number submitted in 2017. Three human rabies deaths were reported in 2018, compared with 2 in 2017. CONCLUSIONS AND CLINICAL RELEVANCE: The overall number of animal rabies cases increased from 2017 to 2018. Laboratory diagnosis of rabies in animals is critical to ensure that human rabies postexposure prophylaxis is administered judiciously.


Assuntos
Doenças do Gato , Doenças dos Bovinos , Quirópteros , Doenças do Cão , Raiva/veterinária , Animais , Animais Domésticos , Animais Selvagens , Gatos , Bovinos , Cães , Equidae , Humanos , New York , North Carolina , Pennsylvania , Vigilância da População , Saúde Pública , Guaxinins , Estados Unidos , Virginia
19.
Trop Med Infect Dis ; 5(1)2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31963635

RESUMO

As a neglected zoonotic disease, rabies causes approximately 5.9 × 104 human deaths annually, primarily affecting low- and middle-income countries in Asia and Africa. In those regions, insufficient surveillance is hampering adequate medical intervention and is driving the vicious cycle of neglect. Where resources to provide laboratory disease confirmation are limited, there is a need for user-friendly and low-cost reliable diagnostic tools that do not rely on specialized laboratory facilities. Lateral flow devices (LFD) offer an alternative to conventional diagnostic methods and may strengthen control efforts in low-resource settings. Five different commercially available LFDs were compared in a multi-centered study with respect to their diagnostic sensitivity and their agreement with standard rabies diagnostic techniques. Our evaluation was conducted by several international reference laboratories using a broad panel of samples. The overall sensitivities ranged from 0% up to 62%, depending on the LFD manufacturer, with substantial variation between the different laboratories. Samples with high antigen content and high relative viral load tended to test positive more often in the Anigen/Bionote test, the latter being the one with the best performance. Still, the overall unsatisfactory findings corroborate a previous study and indicate a persistent lack of appropriate test validation and quality control. At present, the tested kits are not suitable for in-field use for rabies diagnosis, especially not for suspect animals where human contact has been identified, as an incorrect negative diagnosis may result in human casualties. This study points out the discrepancy between the enormous need for such a diagnostic tool on the one hand, and on the other hand, a number of already existing tests that are not yet ready for use.

20.
PLoS Negl Trop Dis ; 13(9): e0007699, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31490919

RESUMO

A subpopulation of the arctic fox lineage of rabies virus has circulated extensively in red fox populations of Ontario, Canada, between the 1960s and 1990s. An intensive wildlife rabies control program, in which field operations were initiated in 1989, resulted in elimination of the disease in eastern Ontario. However in southwestern Ontario, as numbers of rabid foxes declined the proportion of skunks confirmed to be infected with this rabies virus variant increased and concerted control efforts targeting this species were employed to eliminate the disease. Since 2012 no cases due to this viral variant were reported in southwestern Ontario until 2015 when a single case of rabies due to the arctic fox variant was reported in a bovine. Several additional cases have been documented subsequently. Since routine antigenic typing cannot discriminate between the variants which previously circulated in Ontario and those from northern Canada it was unknown whether these recent cases were the result of a new introduction of this variant or a continuation of the previous enzootic. To explore the origins of this new outbreak whole genome sequences of a collection of 128 rabies viruses recovered from Ontario between the 1990s to the present were compared with those representative of variants circulating in the Canadian north. Phylogenetic analysis shows that the variant responsible for current cases in southwestern Ontario has evolved from those variants known to circulate in Ontario previously and is not due to a new introduction from northern regions. Thus despite ongoing passive surveillance the persistence of wildlife rabies went undetected in the study area for almost three years. The apparent adaptation of this rabies virus variant to the skunk host provided the opportunity to explore coding changes in the viral genome which might be associated with this host shift. Several such changes were identified including a subset for which the operation of positive selection was supported. The location of a small number of these amino acid substitutions in or close to protein motifs of functional importance suggests that some of them may have played a role in this host shift.


Assuntos
Raposas/virologia , Vírus da Raiva/isolamento & purificação , Raiva/veterinária , Zoonoses/transmissão , Animais , Animais Selvagens , Bovinos , Doenças dos Bovinos/epidemiologia , Doenças dos Bovinos/virologia , Mephitidae/virologia , Ontário/epidemiologia , Filogenia , Raiva/epidemiologia , Raiva/transmissão , Raiva/virologia , Vírus da Raiva/classificação , Vírus da Raiva/genética , Vírus da Raiva/fisiologia , Zoonoses/epidemiologia , Zoonoses/virologia
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