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1.
Br Dent J ; 231(12): 775-780, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34921276

RESUMO

The Calcivis story is one of innovation and collaboration to deliver new technology capable of helping dentists improve patient care through solving an unmet clinical need in assessing the activity of caries lesions in enamel. Presently, there is no system routinely used in dental practice that can, in a single visit, determine whether a non-cavitated caries lesion is active or not. Calcivis has evolved since 2005, when a potential link between basic science in luminescence and differentiating initial-stage caries lesions that are actively demineralising and likely to progress, from other lesions which are inactive and currently do not need interventive care, was recognised. The 16-year journey has involved clinical academic dentists, scientists and entrepreneurs, general practitioners and their patients, together with serial investors and a core team working to patent, refine, assess and develop products to submit to regulatory approval and take to the international dental market. This journey has been made possible through effective long-term collaborations between disparate groups all sharing a common vision for the possibilities of harnessing new technology to help dental professionals provide better care for their patients.


Assuntos
Suscetibilidade à Cárie Dentária , Cárie Dentária , Cárie Dentária/patologia , Cárie Dentária/terapia , Esmalte Dentário/patologia , Humanos , Tecnologia
2.
Toxicol Pathol ; 49(6): 1193-1205, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34128434

RESUMO

Fetal examinations in embryo-fetal developmental (EFD) studies are based on macroscopic and dissecting microscopic evaluations, and histopathology is rarely performed other than to confirm macroscopic findings. Fetal lens examination is therefore generally limited to the presence, size, shape, and color of any abnormality. In a Sprague-Dawley rat EFD study with the fatty acid amide hydrolase (FAAH) inhibitor JNJ-42165279, an unusually high incidence of macroscopic granular foci was noted within the lens of gestation day 21 fetuses across all groups including controls, with higher incidence in the high-dose group. On histological evaluation of the lenses from fetuses with/without gross findings, primary lens fiber hypertrophy (swelling) and degeneration were observed across vehicle- and JNJ-42165279-exposed fetuses. In a follow-up study to investigate the progression or resolution of the fetal lens changes, animals exposed to suprapharmacological doses of JNJ-42165279 in utero had higher incidence of nuclear cataracts as detected via slit-lamp ophthalmic examinations on postnatal days 18 to 21 and 35 to 41. No histologic correlates for these cataracts were identified. We conclude that fetal primary lens fiber hypertrophy and nuclear cataracts at ophthalmology, are common background changes in this rat strain that are exacerbated by in utero exposure to the FAAH inhibitor JNJ-42165279.


Assuntos
Catarata , Amidoidrolases , Animais , Catarata/induzido quimicamente , Desenvolvimento Fetal , Seguimentos , Piperazinas , Ratos , Ratos Sprague-Dawley
3.
Lancet Infect Dis ; 21(4): 507-516, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33065039

RESUMO

BACKGROUND: The 2013-16 Ebola virus disease epidemic in west Africa caused international alarm due to its rapid and extensive spread resulting in a significant death toll and social unrest within the affected region. The large number of cases provided an opportunity to study the long-term kinetics of Zaire ebolavirus-specific immune response of survivors in addition to known contacts of those infected with the virus. METHODS: In this observational cohort study, we worked with leaders of Ebola virus disease survivor associations in two regions of Guinea, Guéckédou and Coyah, to recruit survivors of Ebola virus disease, contacts from households of individuals known to have had Ebola virus disease, and individuals who were not knowingly associated with infected individuals or had not had Ebola virus disease symptoms to serve as negative controls. We did Zaire ebolavirus glycoprotein-specific T cell analysis on peripheral blood mononuclear cells (PBMCs) on location in Guinea and transported plasma and PBMCs back to Europe for antibody quantification by ELISA, functional neutralising antibody analysis using live Zaire ebolavirus, and T cell phenotype studies. We report on the longitudinal cellular and humoral response among Ebola virus disease survivors and highlight potentially paucisymptomatic infection. FINDINGS: We recruited 117 survivors of Ebola virus disease, 66 contacts, and 23 negative controls. The mean neutralising antibody titre among the Ebola virus disease survivors 3-14 months after infection was 1/174 (95% CI 1/136-1/223). Individual results varied greatly from 1/10 to more than 1/1000 but were on average ten times greater than that induced after 1 month by single dose Ebola virus vaccines. Following reactivation with glycoprotein peptide, the mean T cell responses among 116 Ebola virus disease survivors as measured by ELISpot was 305 spot-forming units (95% CI 257-353). The dominant CD8+ polyfunctional T cell phenotype, as measured among 53 Ebola virus disease survivors, was interferon γ+, tumour necrosis factor+, interleukin-2-, and the mean response was 0·046% of total CD8+ T cells (95% CI 0·021-0·071). Additionally, both neutralising antibody and T cell responses were detected in six (9%) of 66 Ebola virus disease contacts. We also noted that four (3%) of 117 individuals with Ebola virus disease infections did not have circulating Ebola virus-specific antibodies 3 months after infection. INTERPRETATION: The continuous high titre of neutralising antibodies and increased T cell response might support the concept of long-term protective immunity in survivors. The existence of antibody and T cell responses in contacts of individuals with Ebola virus disease adds further evidence to the existence of sub-clinical Ebola virus infection. FUNDING: US Food & Drug Administration, Horizon 2020 EU EVIDENT, Wellcome, UK Department for International Development. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.


Assuntos
Anticorpos Antivirais/sangue , Ebolavirus/imunologia , Doença pelo Vírus Ebola/imunologia , Sobreviventes/estatística & dados numéricos , Linfócitos T/imunologia , Adolescente , Adulto , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/isolamento & purificação , Criança , Pré-Escolar , Ebolavirus/patogenicidade , Epidemias , Feminino , Guiné/epidemiologia , Doença pelo Vírus Ebola/sangue , Doença pelo Vírus Ebola/transmissão , Doença pelo Vírus Ebola/virologia , Humanos , Imunidade Celular , Imunidade Humoral , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem
4.
Clin Pract Cases Emerg Med ; 4(2): 129-133, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32426653

RESUMO

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is caused by the virus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several case series from Italy and China have highlighted the lung ultrasound findings of this disease process and may demonstrate its clinical utility during the current pandemic. CASE REPORT: We present a case of a COVID-19 patient who presented to the emergency department twice within a 24-hour period with rapidly progressing illness. A multi-organ point-of-care ultrasound (POCUS) evaluation was used on the return visit and assisted clinical decision-making. DISCUSSION: A multi-organ POCUS exam allows for quick assessment of acute dyspnea in the emergency department. As the lung involvement of COVID-19 is primarily a peripheral process it is readily identifiable via lung ultrasound. We believe that when applied efficiently and safely a POCUS exam can reduce clinical uncertainty and potentially limit the use of other imaging modalities when treating patients with COVID-19. CONCLUSION: This case highlights the utility of an early multiorgan point-of-care assessment for patients presenting with moderate respiratory distress during the severe SARS-CoV-2 pandemic.

6.
PLoS Negl Trop Dis ; 13(1): e0007026, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30650076

RESUMO

BACKGROUND: Flubendazole, originally developed to treat infections with intestinal nematodes, has been shown to be efficacious in animal models of filarial infections. For treatment of filarial nematodes, systemic exposure is needed. For this purpose, an orally bioavailable amorphous solid dispersion (ASD) formulation of flubendazole was developed. As this formulation results in improved systemic absorption, the pharmacokinetic and toxicological profile of the flubendazole ASD formulation have been assessed to ensure human safety before clinical trials could be initiated. METHODS & FINDINGS: Safety pharmacology, toxicity and genotoxicity studies have been conducted with the flubendazole ASD formulation. In animals, flubendazole has good oral bioavailability from an ASD formulation ranging from 15% in dogs, 27% in rats to more than 100% in jirds. In in vivo toxicity studies with the ASD formulation, high systemic exposure to flubendazole and its main metabolites was reached. Flubendazole, up to high peak plasma concentrations, does not induce Cmax related effects in CNS or cardiovascular system. In repeated dose toxicity studies in rats and dogs, flubendazole-induced changes were observed in haematological, lymphoid and gastrointestinal systems and in testes. In dogs, the liver was an additional target organ. Upon treatment cessation, at least partial recovery was observed for these changes in dogs. In rats, the No Observed Adverse Effect Level (NOAEL) was 5 mg (as base)/kg body weight/day (mg eq./kg/day) in males and 2.5 mg eq./kg/day in females. In dogs, the NOAEL was lower than 20 mg eq./kg/day. Regarding genotoxicity, flubendazole was negative in the Ames test, but positive in the in vivo micronucleus test. CONCLUSIONS: Based on these results, in combination with previously described genotoxicity and reproductive toxicity data and the outcome of the preclinical efficacy studies, it was concluded that no flubendazole treatment regimen can be selected that would provide efficacy in humans at safe exposure.


Assuntos
Antinematódeos/efeitos adversos , Antinematódeos/farmacocinética , Mebendazol/análogos & derivados , Testes de Mutagenicidade , Administração Oral , Animais , Antinematódeos/administração & dosagem , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Gerbillinae , Masculino , Mebendazol/administração & dosagem , Mebendazol/efeitos adversos , Mebendazol/farmacocinética , Ratos Sprague-Dawley
7.
Sci Rep ; 7(1): 2913, 2017 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-28588198

RESUMO

During a proteolytically-driven maturation process, the orthoretroviral capsid protein (CA) assembles to form the convex shell that surrounds the viral genome. In some orthoretroviruses, including Rous Sarcoma Virus (RSV), CA carries a short and hydrophobic spacer peptide (SP) at its C-terminus early in the maturation process, which is progressively removed as maturation proceeds. In this work, we show that RSV CA assembles in vitro at near-physiological temperatures, forming hexamer tubes that effectively model the mature capsid surface. Tube assembly is strongly influenced by electrostatic effects, and is a nucleated process that remains thermodynamically favored at lower temperatures, but is effectively arrested by the large Gibbs energy barrier associated with nucleation. RSV CA tubes are multi-layered, being formed by nested and concentric tubes of capsid hexamers. However the spacer peptide acts as a layering determinant during tube assembly. If only a minor fraction of CA-SP is present, multi-layered tube formation is blocked, and single-layered tubes predominate. This likely prevents formation of biologically aberrant multi-layered capsids in the virion. The generation of single-layered hexamer tubes facilitated 3D helical image reconstruction from cryo-electron microscopy data, revealing the basic tube architecture.


Assuntos
Proteínas do Capsídeo/metabolismo , Vírus do Sarcoma de Rous/fisiologia , Montagem de Vírus , Proteínas do Capsídeo/química , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/ultraestrutura , Imageamento Tridimensional , Técnicas In Vitro , Modelos Moleculares , Concentração Osmolar , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Proteólise , Eletricidade Estática , Temperatura
8.
Reprod Toxicol ; 64: 141-50, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27181369

RESUMO

The fertility study design recommended in the ICH S5(R2) Harmonised Guideline for Detection of Toxicity to Reproduction for Medicinal Products emphasizes the importance of histopathological endpoints next to a pairing assessment in evaluating male fertility. However, in a male rat fertility study with JNJ-26489112, a CNS-active agent, while there were no effects on histological endpoints, mating performance or pregnancy outcomes, sperm assessment was included. The high dose males presented with reversible decreases in epididymal, but not testicular, sperm concentration and motility and an increase in abnormal sperm morphology. In view of the differences in fertility between rats and humans, these types of sperm effects in rats suggest the potential for an impact on human male fertility that would be undetected if not for the sperm assessment. Therefore, the current example suggests that including semenology as a standard endpoint in nonclinical fertility studies may be warranted.


Assuntos
Dioxanos/toxicidade , Fertilidade/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Sulfonamidas/toxicidade , Testes de Toxicidade/métodos , Animais , Relação Dose-Resposta a Droga , Guias como Assunto , Masculino , Ratos Sprague-Dawley , Contagem de Espermatozoides , Motilidade dos Espermatozoides/efeitos dos fármacos , Fatores de Tempo
9.
Reprod Toxicol ; 64: 105-15, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27112527

RESUMO

For pediatric indications requiring juvenile toxicity testing, the rat is the preferred species. However, for some drugs it might not be an appropriate model or regulatory agencies may also request a non-rodent species. Due to the relatively recent use of Göttingen minipigs, little background data are available. This shortage of historical data can raise concerns with respect to interpretation, thus potentially discouraging investigators. This article presents background data from 82 piglets collected at different ages. The data described show the normal variations and changes which are important in the interpretations of these studies. Age-related changes were observed for several cardiac and clinical pathology parameters and in the haematopoietic tissues. Therefore, all pigs were not considered equal. It can be concluded that these data can be used as guidance, to support the concurrent study control data but cannot completely replace them.


Assuntos
Envelhecimento/patologia , Modelos Animais , Porco Miniatura/fisiologia , Suínos/fisiologia , Animais , Animais Recém-Nascidos , Feminino , Masculino , Especificidade de Órgãos , Projetos Piloto , Especificidade da Espécie , Testes de Toxicidade
10.
Reprod Toxicol ; 59: 22-30, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26854737

RESUMO

Small molecule pharmaceutical products are assumed to reach concentrations in semen similar to those in blood plasma. Exposure modeling for these small-molecule products in humans assumes a daily dose of 5mL of semen and 100% absorption from the vagina with distribution to the conceptus through the maternal systemic circulation. Monoclonal antibody drugs are present in semen at concentrations about 2% or less of those in blood, and the modeling used for small molecules will over-estimate the possibility of conceptus exposure to immunoglobulins. It is not known whether peptide products reach semen, but in general peptide medications are destroyed by vaginal peptidases, and conceptus exposure is predicted to be minimal. Theoretical exposure routes to pharmaceuticals that might result in exposure of the conceptus greater than that of maternal systemic exposures include direct access through the cervical canal, adsorption to sperm for carriage into the oocyte, and direct delivery from the vaginal veins or lymphatics to the uterine artery. There is some evidence for direct access to the uterus for progesterone, terbutaline, and danazol, but the evidence does not involve exposures during pregnancy in most instances. Studies in mice, rats, rabbits, and monkeys do not suggest that exposure to small molecule pharmaceuticals in semen imposes risks to the conceptus beyond those that can be predicted using modeling of systemic maternal exposure. Monoclonal antibody and peptide exposure in semen does not pose a significant risk to the conceptus.


Assuntos
Anticorpos Monoclonais/metabolismo , Embrião de Mamíferos/metabolismo , Feto/metabolismo , Peptídeos/metabolismo , Preparações Farmacêuticas/metabolismo , Sêmen/metabolismo , Vagina/metabolismo , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/química , Anticorpos Monoclonais/toxicidade , Transporte Biológico , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Feto/efeitos dos fármacos , Haplorrinos , Humanos , Masculino , Exposição Materna , Camundongos , Modelos Animais , Modelos Biológicos , Exposição Paterna , Peptídeos/química , Peptídeos/toxicidade , Permeabilidade , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Coelhos , Medição de Risco , Absorção Vaginal
11.
Reprod Toxicol ; 59: 1-7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26546978

RESUMO

Risk assessment for indirect exposure to small molecule pharmaceuticals in semen to the conceptus has traditionally been handled by calculations based on assumptions that any embryo-fetal exposure would be secondary to maternal absorption and redistribution. This study was designed to assess the potential for transcervical passage of drugs from semen. Reproductive tracts of rodents were examined following vaginal dosing with vital dyes during the estrous cycle, mating, and pregnancy. Toluidine Blue was not observed beyond the cervix after vaginal administration in pregnant rats; additionally, it did not pass the cervix in rats during any phase of estrous. In order to address the effects of semen, rats were dosed at receptivity and mated. Vital dyes were not visually evident in the uterus despite vaginal and sperm plug staining. This study provides evidence that direct transcervical passage is not a substantial route of direct embryo-fetal exposure for small molecule drugs in semen.


Assuntos
Colo do Útero/metabolismo , Corantes/metabolismo , Sêmen/metabolismo , Comportamento Sexual Animal , Cloreto de Tolônio/metabolismo , Administração Intravaginal , Animais , Corantes/administração & dosagem , Feminino , Idade Gestacional , Masculino , Exposição Materna , Camundongos Endogâmicos ICR , Exposição Paterna , Permeabilidade , Gravidez , Ratos Sprague-Dawley , Fatores de Tempo , Cloreto de Tolônio/administração & dosagem , Vagina/metabolismo
12.
Reprod Toxicol ; 58: 213-21, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26545974

RESUMO

Small molecule pharmaceutical products are assumed to reach concentrations in semen similar to those in blood plasma. Exposure modeling for these small-molecule products in humans assumes a daily dose of 5mL of semen and 100% absorption from the vagina with distribution to the conceptus through the maternal systemic circulation. Monoclonal antibody drugs are present in semen at concentrations about 2% or less of those in blood, and the modeling used for small molecules will over-estimate the possibility of conceptus exposure to immunoglobulins. It is not known whether peptide products reach semen, but in general peptide medications are destroyed by vaginal peptidases, and conceptus exposure is predicted to be minimal. Theoretical exposure routes to pharmaceuticals that might result in exposure of the conceptus greater than that of maternal systemic exposures include direct access through the cervical canal, adsorption to sperm for carriage into the oocyte, and direct delivery from the vaginal veins or lymphatics to the uterine artery. There is some evidence for direct access to the uterus for progesterone, terbutaline, and danazol, but the evidence does not involve exposures during pregnancy in most instances. Studies in mice, rats, rabbits, and monkeys do not suggest that exposure to small molecule pharmaceuticals in semen imposes risks to the conceptus beyond those that can be predicted using modeling of systemic maternal exposure. Monoclonal antibody and peptide exposure in semen does not pose a significant risk to the conceptus.


Assuntos
Anticorpos Monoclonais/metabolismo , Colo do Útero/metabolismo , Embrião de Mamíferos/metabolismo , Preparações Farmacêuticas/metabolismo , Proteínas/metabolismo , Sêmen/metabolismo , Vagina/metabolismo , Animais , Anticorpos Monoclonais/efeitos adversos , Transporte Biológico , Colo do Útero/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Humanos , Masculino , Modelos Biológicos , Gravidez , Proteínas/efeitos adversos , Medição de Risco , Fatores de Risco , Especificidade da Espécie , Vagina/efeitos dos fármacos
13.
J Endod ; 40(7): 1013-9, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24935555

RESUMO

INTRODUCTION: A case of a symptomatic maxillary central incisor that underwent periradicular regenerative surgery with a successful long-term clinical and radiographic outcome is presented. METHODS: A 52-year old woman was referred to the Endodontology Clinic, UCL Eastman Dental Institute and Hospital, London, UK, in 2004 for swelling and discoloration of the maxillary right central incisor. There was a history of trauma 21 years previously. The tooth was endodontically treated 5 years before the referral. At presentation, there was diffuse facial swelling/erythema and a periodontal probing depth of 11 mm on the midfacial surface with bleeding on probing and purulent exudate. Endodontic retreatment was completed along with subgingival debridement. Reassessment at 6 weeks showed persistent purulent exudate and a probing depth up to 13 mm facially. Periradicular surgery was performed for the purposes of surgical exploration, apical resection and root-end filling with mineral trioxide aggregate, and guided tissue regeneration using a bone xenograft and collagen membrane. Histopathology confirmed the presence of a radicular cyst. RESULTS: Clinical and radiographic evaluation, including cone-beam computed tomographic imaging, at 7 years postoperatively showed a probing depth up to 3 mm and hard tissue formation apically, interproximally, and partly facially on the root surface. CONCLUSIONS: In this case of a combined endodontic-periodontic lesion in a maxillary central incisor, regenerative periradicular surgery led to the resolution of the defect, significant attachment gain, and a stable clinical and radiographic outcome after 7 years of follow-up.


Assuntos
Apicectomia/métodos , Tomografia Computadorizada de Feixe Cônico/métodos , Regeneração Tecidual Guiada Periodontal/métodos , Incisivo/cirurgia , Obturação Retrógrada/métodos , Dente não Vital/cirurgia , Compostos de Alumínio/uso terapêutico , Transplante Ósseo/métodos , Compostos de Cálcio/uso terapêutico , Colágeno , Desbridamento/métodos , Combinação de Medicamentos , Feminino , Seguimentos , Xenoenxertos/transplante , Humanos , Incisivo/diagnóstico por imagem , Maxila , Membranas Artificiais , Pessoa de Meia-Idade , Óxidos/uso terapêutico , Abscesso Periapical/cirurgia , Perda da Inserção Periodontal/cirurgia , Bolsa Periodontal/cirurgia , Cisto Radicular/cirurgia , Retratamento , Materiais Restauradores do Canal Radicular/uso terapêutico , Silicatos/uso terapêutico , Dente não Vital/diagnóstico por imagem , Resultado do Tratamento
14.
Vet Parasitol ; 196(1-2): 96-105, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23384579

RESUMO

Cattle within seven NSW herds with a history or risk of clinical Theileria orientalis disease associated with introductions of cattle were examined clinically and by haematological and PCR testing at sequential bleeds or at single sampling of different risk subgroups. The T. orientalis Ikeda type was detected in all herds and Chitose type was detected in six. Pale and jaundiced mucosal surfaces were associated with clinically affected groups of cattle, and herds containing cattle with ≥ 1% theilerias in erythrocytes were associated with high prevalence of Ikeda type, with or without Chitose type. In clinically normal cattle within these Ikeda-affected herds, over half of the smear negative animals were detected as infected with Ikeda type, while 90% of smear positive cases were positive for Ikeda type. Infection with Ikeda and Chitose organisms was detected in calves as young as 1-2 weeks, rapidly increased in prevalence within one month and was maintained until 4.5 months of age. In these calves Ikeda prevalence increased at a faster rate than the other MPSP types, particularly Buffeli which is generally considered to be avirulent, and suggests either an increased growth rate or rate of transmission of the Ikeda type or failure of the host immune system to clear this type. Particularly high T. orientalis prevalence rates were detected (in blood samples from a single time point) in adults that had been in direct contact with weaner cattle introduced from coastal areas; however, the lack of direct contact with affected cattle did not prevent infection with Ikeda type in some cases. Spread within previously naïve herds was variable, and results also depended on the sampling time point. In contrast, groups in which infection was already established gave repeatedly similar results at multiple samplings taken at one month intervals. Our results confirm that a large reservoir of infected but clinically normal animals exists within T. orientalis-affected cattle herds and PCR testing of EDTA bloods is more sensitive for detecting subclinical infection than blood smear examination. Direct contact with weaner cattle introduced from coastal areas appears to be a major risk factor for T. orientalis infection in adult cattle. Frequent sampling may be used to monitor spread of T. orientalis within newly affected herds, but may be unrewarding once a high prevalence is established.


Assuntos
Reação em Cadeia da Polimerase/veterinária , Theileria/classificação , Theileriose/parasitologia , Animais , Bovinos , Feminino , Masculino , New South Wales/epidemiologia , Reação em Cadeia da Polimerase/métodos , Prevalência , Sensibilidade e Especificidade , Theileriose/diagnóstico , Theileriose/epidemiologia
15.
Vet Parasitol ; 191(3-4): 209-17, 2013 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-23044251

RESUMO

Between September 2010 and November 2011, 350 EDTA blood samples were received from 73 Australian cattle herds, as cases suspected to be infected with Theileria orientalis. Beef cattle were predominantly affected, with Angus and Angus-crossbred cattle representing 48% of smear positive samples examined. DNA extracts were tested in conventional polymerase chain reaction (PCR) assays for genes encoding the p32, Ikeda, Chitose and Buffeli major piroplasm surface proteins (MPSP). PCR findings were compared with results of clinical pathology examinations of stained blood smears for parasitaemia and packed cell volume (PCV). PCR testing was much more sensitive than clinical pathology examinations in detecting T. orientalis infections, and concurrent testing of neat and diluted extracts gave significantly more PCR positive results than testing of neat extract alone. Significant associations and correlations were shown between PCR results of p32 and Ikeda assays with PCV levels indicative of anaemia, and with the level of parasitaemia estimated by smears. A high proportion of samples had concurrent Ikeda and Chitose infection, and significantly more clinical cases of theileriosis were associated with the Ikeda MPSP type as the sole infection, compared with sole infection with types Chitose or Buffeli. The findings indicate Ikeda type organisms were significantly associated with clinical parameters of theileriosis in cattle herds in eastern Australia, and that this type is most likely to be responsible for outbreaks of theileriosis experienced in affected Australian herds. In New South Wales, 11 of 14 regulatory districts yielded Ikeda positive samples, with five (Mid-Coast, Cumberland, Central North, Hume and Lachlan) containing 234/307 (76%) of the Ikeda positive samples.


Assuntos
Antígenos de Protozoários/genética , Proteínas de Protozoários/genética , Theileria/genética , Theileriose/patologia , Theileriose/parasitologia , Animais , Austrália/epidemiologia , Bovinos , Surtos de Doenças , Genes de Protozoários/genética , Reação em Cadeia da Polimerase , Theileriose/diagnóstico , Theileriose/epidemiologia
17.
J Mol Biol ; 417(3): 212-23, 2012 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-22306463

RESUMO

The genome of a retrovirus is surrounded by a convex protein shell, or capsid, that helps facilitate infection. The major part of the capsid surface is formed by interlocking capsid protein (CA) hexamers. We report electron and X-ray crystallographic analysis of a variety of specimens assembled in vitro from Rous sarcoma virus (RSV) CA. These specimens all contain CA hexamers arranged in planar layers, modeling the authentic capsid surface. The specimens differ only in the number of layers incorporated and in the disposition of each layer with respect to its neighbor. The body of each hexamer, formed by the N-terminal domain of CA, is connected to neighboring hexamers through C-terminal domain dimerization. The resulting layer structure is very malleable due to inter-domain flexibility. A helix-capping hydrogen bond between the two domains of RSV CA creates a pivot point, which is central to controlling their relative movement. A similar mechanism for the governance of inter-domain motion was recently described for the human immunodeficiency virus type 1 (HIV-1) capsid, although there is negligible sequence identity between RSV and HIV-1 CA in the region of contact, and the amino acids involved in creating the pivot are not conserved. Our observations allow development of a physically realistic model for the way neighboring hexamers can tilt out of plane, deforming the hexamer layer and generating the continuously curved surfaces that are a feature of all retroviral capsids.


Assuntos
Capsídeo/química , Vírus do Sarcoma de Rous/química , Cristalografia por Raios X , HIV-1/química , Ligação de Hidrogênio , Microscopia Eletrônica de Transmissão , Modelos Moleculares , Conformação Proteica , Multimerização Proteica , Estrutura Terciária de Proteína
18.
Reprod Toxicol ; 32(2): 149, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21683782
19.
Birth Defects Res B Dev Reprod Toxicol ; 92(4): 273-91, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22623019

RESUMO

Recent changes in the regulations from the FDA and EMA have shifted the focus of juvenile toxicity studies more to the safe use of all pharmaceuticals and the absence of label or safety information for the pediatric population. Unlike other regulatory guidance, the need or design of these animal studies is not specified. Ideally these should be decided "case-by-case" based on the patient population, pharmacology, existing toxicological and clinical data, dosing regimen, and developing system impact. Following the publishing of a small intercompany survey (Bailey and Mariën, 2009), a more extensive survey was commissioned by the ILSI/HESI DART Technical Committee to clarify what has been learned for the safety assessment for pediatrics. Contributions from 24 companies totaling 241 studies (84% rat and 14% dog) were received. In 12 of 82 programs (15%) were the existing adult preclinical or clinical data considered a sufficient safety prediction for pediatric trials. Clinical/preclinical correlates were observed in 17.2% (rat) and 42.9% (dog) of the studies and a lack of predictability from the pharmacology or the adult toxicity data was seen in 25% of rat and 14.3% of dog studies. Many of the studies were large, lengthy, complex, included parameters that mirrored the adult studies and yielded no new or useful information. We should avoid conducting complex or inappropriate studies and Contract Research Organisations and regulatory agencies have a role in encouraging more targeted designs. Only with appropriate designs can we adequately identify safety or pharmacokinetic issues, suggest clinical endpoints, and contribute to the product label.


Assuntos
Animais de Laboratório/crescimento & desenvolvimento , Drogas em Investigação , Modelos Animais , Pediatria , Projetos de Pesquisa , Testes de Toxicidade , Adulto , Animais , Criança , Cães , Avaliação de Medicamentos , Humanos , Ratos
20.
Birth Defects Res B Dev Reprod Toxicol ; 92(4): 292-303, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22623020

RESUMO

The Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute has undertaken a project to address the impact of juvenile animal studies on pediatric drug development. A workshop, sponsored and organized by the Health and Environmental Sciences Institute Developmental and Reproductive Toxicity Technical Committee, was held on May 5-6, 2010, in Washington, DC, to discuss the outcome of a global survey and the value of juvenile animal studies in the development of drugs intended for use in pediatric patients. During this workshop, summary data from the 2009-2010 survey were presented, and breakout sessions were used to discuss specific case studies to try to assess the impact of juvenile animal studies performed to support specific pediatric drug development. The objectives of the Workshop on The Value of Juvenile Animal Studies were to (1) provide a forum for scientists representing industry, academia, and regulatory agencies to discuss the impact of juvenile animal studies on pediatric drug development, (2) evaluate summary data from the survey to understand how the juvenile study data are being used and their impact in labeling and risk assessment, (3) discuss selected case studies from the survey to highlight key findings, and (4) identify the areas of improvement for the designs of juvenile animal studies. The take home message that resonated from the workshop discussions was that well-designed juvenile animal studies have demonstrated value in support of certain pediatric drug development programs. However, it was also clear that a juvenile animal study is not always warranted.


Assuntos
Animais de Laboratório/crescimento & desenvolvimento , Avaliação Pré-Clínica de Medicamentos , Modelos Animais , Animais , Medição de Risco , Testes de Toxicidade
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