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BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is highly heritable and is associated with lower educational attainment. ADHD is linked to family adversity, including hostile parenting. Questions remain regarding the role of genetic and environmental factors underlying processes through which ADHD symptoms develop and influence academic attainment. METHOD: This study employed a parent-offspring adoption design (N = 345) to examine the interplay between genetic susceptibility to child attention problems (birth mother ADHD symptoms) and adoptive parent (mother and father) hostility on child lower academic outcomes, via child ADHD symptoms. Questionnaires assessed birth mother ADHD symptoms, adoptive parent (mother and father) hostility to child, early child impulsivity/activation, and child ADHD symptoms. The Woodcock-Johnson test was used to examine child reading and math aptitude. RESULTS: Building on a previous study (Harold et al., 2013, Journal of Child Psychology and Psychiatry, 54(10), 1038-1046), heritable influences were found: birth mother ADHD symptoms predicted child impulsivity/activation. In turn, child impulsivity/activation (4.5 years) evoked maternal and paternal hostility, which was associated with children's ADHD continuity (6 years). Both maternal and paternal hostility (4.5 years) contributed to impairments in math but not reading (7 years), via impacts on ADHD symptoms (6 years). CONCLUSION: Findings highlight the importance of early child behavior dysregulation evoking parent hostility in both mothers and fathers, with maternal and paternal hostility contributing to the continuation of ADHD symptoms and lower levels of later math ability. Early interventions may be important for the promotion of child math skills in those with ADHD symptoms, especially where children have high levels of early behavior dysregulation.
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Sucesso Acadêmico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Interação Gene-Ambiente , Relações Pais-Filho , Adulto , Criança , Comportamento Infantil/psicologia , Criança Adotada/psicologia , Pré-Escolar , Feminino , Hostilidade , Humanos , Comportamento Impulsivo , Estudos Longitudinais , Masculino , Poder Familiar/psicologia , Pais/psicologiaRESUMO
The isolation of Salmonella from feed is challenging and adjustments need to be made in order to accurately isolate the pathogen from feed. This is due to the complex nature of the feed matrix, which is both porous and fibrous. The outlined method below contains the essential components of a successful Salmonella methodology for the analysis of feed that overcomes the limitations of currently available methods.
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Ração Animal/microbiologia , Salmonella/isolamento & purificação , Animais , Microbiologia de Alimentos/métodosRESUMO
Understanding the interplay between genetic factors and family environmental processes (e.g., inter-parental relationship quality, positive versus negative parenting practices) and children's mental health (e.g., anxiety, depression, conduct problems, ADHD) in the contexts of adoption and foster-care research and practice is critical for effective prevention and intervention programme development. Whilst evidence highlights the importance of family environmental processes for the mental health and well-being of children in adoption and foster care, there is relatively limited evidence of effective interventions specifically for these families. Additionally, family-based interventions not specific to the context of adoption and foster-care typically show small to medium effects, and even where interventions are efficacious, not all children benefit. One explanation for why interventions may not work well for some is that responses to intervention may be influenced by an individual's genetic make-up. This paper summarises how genetically-informed research designs can help disentangle genetic from environmental processes underlying psychopathology outcomes for children, and how this evidence can provide improved insights into the development of more effective preventative intervention targets for adoption and foster-care families. We discuss current difficulties in translating behavioural genetics research to prevention science, and provide recommendations to bridge the gap between behavioural genetics research and prevention science, with lessons for adoption and foster-care research and practice.
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BACKGROUND AND OBJECTIVE: Periodontitis results from interplay between genetic and environmental factors. Single nucleotide polymorphisms (SNPs) in the coding region of the toll-like receptor 4 gene (TLR4) may be associated with periodontitis, although previous studies have been inconclusive. Moreover, the interaction between environmental factors, such as cigarette smoking (a major risk factor for periodontitis), and Porphyromonas gingivalis (a major periodontal pathogen) with the TLR4 coding region Asp299Gly SNP (rs4986790; a SNP associated with lipopolysaccharide-mediated inflammatory responses in periodontitis), have been largely ignored in previous reports. Therefore, the objective of this study was to examine the association between TLR4 Asp299Gly (rs4986790) with alveolar bone height loss (ABHL) and periodontitis, accounting for interactions between this SNP with smoking and P. gingivalis prevalence. The CD14/-260 SNP (rs2569190) served as a control, as a recent meta-analysis suggested no relationship between this SNP and periodontitis. MATERIAL AND METHODS: This multicenter study included 617 participants who had rheumatoid arthritis or osteoarthritis. This report presents a secondary outcome from the primary case-control study examining the relationship of periodontitis with established rheumatoid arthritis. The Centers for Disease Control/American Academy of Periodontology case definitions of periodontitis were used for this analysis. Participants received a full-mouth clinical periodontal examination and panoramic radiograph. Percentage ABHL was measured on posterior teeth. The TLR4 Asp299Gly and CD14/-260 SNPs were selected a priori and genotypes were determined using the ImmunoChip array (Illumina(®) ). Minor allele frequencies and associations with periodontitis and ABHL did not differ according to rheumatoid arthritis vs. osteoarthritis status; therefore, data from these two groups were pooled. The presence of P. gingivalis was detected in subgingival plaque by PCR. Multivariate ordinal logistic regression examined associations between the SNPs and periodontitis or ABHL. SNP interactions with smoking and P. gingivalis were analyzed. RESULTS: A significant, negative interaction was observed between the TLR4 SNP and the presence of P. gingivalis (p = 0.045) with respect to periodontitis. The TLR4 minor variant was also associated with less ABHL: 16.8% of individuals with low ABHL, 9.0% with moderate ABHL and 11.2% with high ABHL had the minor allele [p = 0.029; odds ratio = 0.58 (95% confidence interval: 0.36-0.95)]. The interaction between the TLR4 SNP and smoking was not significant with respect to periodontitis or ABHL. The CD14 SNP was not associated with periodontitis or ABHL. CONCLUSION: The TLR4 Asp299Gly SNP significantly interacted with P. gingivalis in conferring a decreased risk of periodontitis and may be protective against ABHL, a feature of periodontitis. Agents blocking TLR4 signaling, a strategy currently under investigation for the treatment of other inflammatory conditions, may warrant investigation in the context of periodontitis related to the presence of P. gingivalis.
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Periodontite Crônica/genética , Polimorfismo de Nucleotídeo Único , Receptor 4 Toll-Like/genética , Estudos de Casos e Controles , Humanos , Periodontite , Porphyromonas gingivalisRESUMO
Embryonic stem cells have had a significant impact on understanding gene function and gene interactions through the use of genetically engineered mice. However, the genetic context (ie, mouse strain) in which these modifications in alleles are made may have a considerable effect on the phenotypic changes identified in these mice. In addition, tissue- and time-specific gene expression systems may generate unanticipated outcomes. This article discusses the history of embryonic stem cells, reviews how mouse strain can affect phenotype (using specific examples), and examines some of the caveats of conditional gene expression systems.
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Células-Tronco Embrionárias , Variação Genética/genética , Camundongos Transgênicos/classificação , Fenótipo , Alelos , Animais , Expressão Gênica/genética , Engenharia Genética , Camundongos , Mutação , Especificidade de Órgãos , Fatores de Tempo , TransgenesRESUMO
Inbred laboratory mouse strains are highly divergent in their immune response patterns as a result of genetic mutations and polymorphisms. The generation of genetically engineered mice (GEM) has, in the past, used embryonic stem (ES) cells for gene targeting from various 129 substrains followed by backcrossing into more fecund mouse strains. Although common inbred mice are considered "immune competent," many have variations in their immune system-some of which have been described-that may affect the phenotype. Recognition of these immune variations among commonly used inbred mouse strains is essential for the accurate interpretation of expected phenotypes or those that may arise unexpectedly. In GEM developed to study specific components of the immune system, accurate evaluation of immune responses must take into consideration not only the gene of interest but also how the background strain and microbial milieu contribute to the manifestation of findings in these mice. This article discusses points to consider regarding immunological differences between the common inbred laboratory mouse strains, particularly in their use as background strains in GEM.
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Camundongos Endogâmicos/imunologia , Camundongos Transgênicos/imunologia , Modelos Animais , Mutação , Fenótipo , Polimorfismo Genético/imunologia , Animais , Feminino , Engenharia Genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos/classificação , Camundongos Endogâmicos/genética , Camundongos Transgênicos/classificação , Camundongos Transgênicos/genéticaRESUMO
The phenotype of genetically engineered mice is a combination of both genetic and environmental factors that include the microflora of the mouse. The impact a particular microbe has on a mouse reflects the host-microbe interaction within the context of the mouse genotype and environment. Although often considered a confounding variable, many host-microbe interactions have resulted in the generation of novel model systems and characterization of new microbial agents. Microbes associated with overt disease in mice have been the historical focus of the laboratory animal medical and pathology community and literature. The advent of genetic engineering and the complex of mouse models have revealed previously unknown or disregarded agents that now oblige the attention of the biomedical research community. The purpose of this article is to describe and illustrate how phenotypes can be affected by microflora by focusing on the infectious diseases present in genetically engineered mouse (GEM) colonies of our collective institutions and by reviewing important agents that are rarely seen in most research facilities today. The goal is to introduce the concept of the role of microflora on phenotypes and in translational research using GEM models.
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Doenças Transmissíveis/veterinária , Modelos Animais de Doenças , Camundongos Transgênicos , Fenótipo , Doenças dos Roedores/microbiologia , Doenças dos Roedores/parasitologia , Animais , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/parasitologia , Engenharia Genética , Humanos , Camundongos , Doenças dos Roedores/genética , Organismos Livres de Patógenos EspecíficosRESUMO
Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid into prostaglandin H(2) (PGH(2)), which is subsequently converted to the prostanoids PGE(2), PGI(2), PGF(2alpha), and thromboxane A(2). COX has 2 distinct membrane-anchored isoenzymes: COX-1 and COX-2. COX-1 is constitutively expressed in most normal tissues; COX-2 is highly induced by proinflammatory mediators in the setting of inflammation, injury, and pain. Inhibitors of COX activity include conventional nonselective nonsteroidal anti-inflammatory drugs and selective nonsteroidal anti-inflammatory drugs, such as COX-2 inhibitors. The adverse effects of COX inhibitors on the cardiovascular system have been addressed in the last few years. In general, COX inhibitors have many effects, but those most important to the cardiovascular system can be direct (through the effects of prostanoids) and indirect (through alterations in fluid dynamics). Despite reports of detrimental human cardiovascular events associated with COX inhibitors, short, long, and lifetime preclinical toxicology studies in rodents and nonrodents have failed to identify these risks. This article focuses on the expression and function of COX enzymes in normal and pathologic conditions of the cardiovascular system and discusses the cardiovascular pathophysiologic complications associated with COX inhibition.
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Sistema Cardiovascular/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Homeostase/efeitos dos fármacos , Animais , Inibidores de Ciclo-Oxigenase/efeitos adversos , Inibidores de Ciclo-Oxigenase/uso terapêutico , Humanos , CamundongosRESUMO
PURPOSE: Currently there is no satisfactory treatment for metastatic melanoma. Radioimmunotherapy (RIT) uses the antigen-antibody interaction to deliver lethal radiation to target cells. Recently we established the feasibility of targeting melanin in tumors with 188-Rhenium ((188)Re)-labeled 6D2 mAb to melanin. Here we carried out pre-clinical development of (188)Re-6D2 to accrue information necessary for a Phase I trial in patients with metastatic melanoma. RESULTS: TCEP proved to be effective in generating a sufficient number of -SH groups on 6D2 to ensure high radiolabeling yields with (188)Re and preserved its structural integrity. (188)Re-6D2 was quickly cleared from the blood with the half-life of approximately 5 hrs and from the body--with the half-life of 10 hr. The doses of 0.5, 1.0 and 1.5 mCi significantly (p < 0.05) slowed down A2058 tumor growth in nude mice, also causing release of melanin into the extracellular space which could provide additional target for repeated treatments. Transient effects of RIT on WBC and platelet counts resolved by Day 14 post-treatment. EXPERIMENTAL DESIGN: Tris(2-Carboxyethyl) Phosphine Hydrochloride (TCEP) was evaluated as potential agent for generation of -SH groups on 6D2 mAb. TCEP-treated 6D2 mAb was radiolabeled with (188)Re and its radiochemical purity and stability was measured by ITLC and HPLC and its immunoreactivity--by melanin-binding ELISA. The pharmacokinetics, therapeutic efficacy and acute hematologic toxicity studies were performed in nude mice bearing lightly pigmented A2058 human metastatic melanoma tumors. CONCLUSIONS: We have developed radiolabeling and quality control procedures for melanin-binding (188)Re-6D2 mAb which made possible currently an on-going Phase I clinical trial in patients with metastatic melanoma.
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Ensaios de Seleção de Medicamentos Antitumorais , Imunoglobulina M/química , Melaninas/química , Animais , Ácido Ascórbico/química , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Camundongos , Camundongos Nus , Metástase Neoplásica , Transplante de Neoplasias , Radioimunoterapia/métodos , Radioisótopos/farmacologia , Rênio/farmacologiaRESUMO
John Brooksby was an outstanding veterinary virologist, who worked at the Animal Virus Disease Research Institute, Pirbright, for 40 years, for 16 of which he was Director of the Institute. He will be remembered for his contributions to the diagnosis of foot-and-mouth disease, for his discovery of four new types, for the classification of subtypes and for fundamental studies of the virus. As Deputy Director and Director he was responsible for programmes on fundamental investigations of foot-and-mouth disease virus and other viruses exotic to the UK and for the application of the results both in the UK and worldwide. His advice on the distribution and the control of foot-and-mouth disease was sought by international organizations and by individual countries and was responsible for reducing the risk of spread of disease.
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Vírus da Febre Aftosa , Febre Aftosa/classificação , Febre Aftosa/diagnóstico , Febre Aftosa/história , Febre Aftosa/prevenção & controle , Medicina Veterinária , África , Animais , Bovinos , Enterovirus Suínos/classificação , Enterovirus Suínos/patogenicidade , Febre Aftosa/epidemiologia , Febre Aftosa/etiologia , Febre Aftosa/genética , Febre Aftosa/microbiologia , Vírus da Febre Aftosa/classificação , Vírus da Febre Aftosa/genética , Vírus da Febre Aftosa/imunologia , Vírus da Febre Aftosa/patogenicidade , História do Século XX , Saúde Pública/história , Saúde Pública/métodos , Pesquisa/história , Pesquisa/organização & administração , Projetos de Pesquisa , Doença Vesicular Suína/diagnóstico , Doença Vesicular Suína/história , Reino Unido , Medicina Veterinária/história , Medicina Veterinária/métodos , Virologia/classificação , Virologia/história , Virologia/métodos , Recursos HumanosRESUMO
The measures used to control the epidemics of foot-and-mouth disease in Canada in 1951/52 (29 outbreaks) were compared with those used in the epidemic in Hampshire in 1967 (29 outbreaks). In both epidemics the disease spread more from premises where the disease was reported late and the imposition of quarantine or restrictions on infected premises was delayed. In Hampshire, area restrictions were imposed, susceptible livestock on infected premises and on premises in direct contact were slaughtered, and contacts were traced. In Canada, the initial diagnosis was vesicular stomatitis, no area restrictions were imposed, no tracing was carried out and the animals on infected premises were allowed to recover. However, apart from the disease's spread through infected meat and by unknown or airborne routes, it did not spread from infected premises once quarantine was imposed, partly owing to the low population density of livestock in the area. The effects of the slaughter of infected premises and direct contacts in the Fareham area of Hampshire in 1967 and in the Chathill area of Northumberland in 1966 were compared with what might have happened if, in addition, culling on contiguous premises or culling on premises within 3 km or emergency vaccination had been put into effect. The slaughter of cattle, sheep, goats and pigs on premises within 3 km two days after confirmation of the first outbreak would have resulted in fewer outbreaks and a shorter period to complete slaughter, but more animals would have been slaughtered. In the Chathill area, the slaughter of sheep, goats and pigs only on premises within 3 km two days after confirmation of the first outbreak would not have resulted in fewer outbreaks and more animals would have been slaughtered. Fewer premises and animals would have been slaughtered by a contiguous cull than by a 3 km cull but more than by the slaughter of infected premises and direct contacts. Emergency vaccination within 3 km, providing protection at four days (but not to animals already infected before the development of immunity), would have resulted in the fewest animals being slaughtered and could have reduced the number of outbreaks in the Fareham area by one and in the Chathill area by two or three. All the procedures would have had a greater effect the sooner they were introduced. However, with many foci of infection, priorities for action would have had to have been established. Earlier tracing of the last outbreak in the Fareham area could have shortened the Hampshire epidemic. Surveillance of a farm identified as at risk through animal movements and by the use of an airborne-prediction model could have eliminated the source of further outbreaks in the Chathill area.
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Surtos de Doenças/prevenção & controle , Surtos de Doenças/veterinária , Febre Aftosa/epidemiologia , Febre Aftosa/prevenção & controle , Quarentena/veterinária , Animais , Canadá/epidemiologia , Bovinos , Inglaterra/epidemiologia , Eutanásia Animal , Cabras , Ruminantes , Ovinos , Suínos , Vacinação/veterináriaRESUMO
The likelihood of airborne spread of foot-and-mouth disease at the start of the 1967-1968 epidemic is re-assessed in the light of current understanding of airborne disease spread. The findings strongly confirm those made at the time that airborne virus was the most likely cause of the rapid early development of the disease out to 60 km from the source. This conclusion is reached following a detailed epidemiological, meteorological and modelling study using original records and current modelling techniques. The role played by 'lee waves' as the mechanism for the spread is investigated. It is thought that they played little part in influencing the development of the epidemic. A number of lessons learned from the work are drawn, identifying the need for further research on the quantity and characteristics of airborne virus. The results are also used to illustrate what advice would have been available to disease controllers if the outbreak had occurred in 2004.
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Microbiologia do Ar , Surtos de Doenças/veterinária , Transmissão de Doença Infecciosa/veterinária , Febre Aftosa/epidemiologia , Febre Aftosa/transmissão , Animais , Atmosfera , Bovinos , Febre Aftosa/virologia , Modelos Teóricos , Ovinos , Suínos , Reino Unido/epidemiologiaRESUMO
Parathyroid hormone-related protein (PTHrP) is a multifunctional protein that is often dysregulated in cancer. The human PTHrP gene is alternatively spliced into three isoforms, each with a unique 3'-untranslated region (3'-UTR), encoding 139, 173 and 141 amino acid proteins. The regulation of PTHrP mRNA isoform expression has not been completely elucidated, but it may be affected by transforming growth factor-beta1 (TGF-beta1). In this study, we examined differences in the PTHrP mRNA isoform expression in two squamous carcinoma cell lines (SCC2/88 and HARA), an immortalized keratinocyte cell line (HaCaT), and spontaneous human lung cancer with adjacent normal tissue. In addition, the effect of TGF-beta1 on PTHrP mRNA isoform expression and stability was examined. Cell-type specific expression of PTHrP mRNA isoforms occurred between the various cell lines, normal human lung, and immortalized human keratinocytes (HaCaT). PTHrP isoform expression pattern was significantly altered between normal lung tissue and the adjacent lung cancer. In vitro studies revealed that TGF-beta1 differentially altered the mRNA steady-state levels and mRNA stability of the PTHrP isoforms. Protein-RNA binding studies identified different proteins binding to the 3'-UTR of the PTHrP isoforms (139) and (141), which may be important in the differential mRNA stability and response to cytokines between the PTHrP isoforms. The data demonstrate that there is cell-type specific expression of PTHrP mRNA isoforms, and disruption of the normal regulation during cancer progression may in part be associated with TGF-beta1-induced changes in PTHrP mRNA isoform expression and stability.