RESUMO
Animals and animal models have been invaluable for our current understanding of human and animal biology, including physiology, pharmacology, biochemistry, and disease pathology. However, there are increasing concerns with continued use of animals in basic biomedical, pharmacological, and regulatory research to provide safety assessments for drugs and chemicals. There are concerns that animals do not provide sufficient information on toxicity and/or efficacy to protect the target population, so scientists are utilizing the principles of replacement, reduction, and refinement (the 3Rs) and increasing the development and application of new approach methods (NAMs). NAMs are any technology, methodology, approach, or assay used to understand the effects and mechanisms of drugs or chemicals, with specific focus on applying the 3Rs. Although progress has been made in several areas with NAMs, complete replacement of animal models with NAMs is not yet attainable. The road to NAMs requires additional development, increased use, and, for regulatory decision making, usually formal validation. Moreover, it is likely that replacement of animal models with NAMs will require multiple assays to ensure sufficient biologic coverage. The purpose of this manuscript is to provide a balanced view of the current state of the use of animal models and NAMs as approaches to development, safety, efficacy, and toxicity testing of drugs and chemicals. Animals do not provide all needed information nor do NAMs, but each can elucidate key pieces of the puzzle of human and animal biology and contribute to the goal of protecting human and animal health. SIGNIFICANCE STATEMENT: Data from traditional animal studies have predominantly been used to inform human health safety and efficacy. Although it is unlikely that all animal studies will be able to be replaced, with the continued advancement in new approach methods (NAMs), it is possible that sometime in the future, NAMs will likely be an important component by which the discovery, efficacy, and toxicity testing of drugs and chemicals is conducted and regulatory decisions are made.
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Testes de Toxicidade , Animais , Humanos , Testes de Toxicidade/métodos , Modelos AnimaisRESUMO
Molar-incisor hypomineralisation (MIH) is a qualitative defect of the enamel structure. Indirect restorations may represent the most suitable therapeutic solutions for patients presenting MIH with tooth restorative procedures. This systematic review aims to determine the feasibility of indirect restorations. MATERIALS AND METHODS: A systematic review has been performed and is reported following the PRISMA guidelines. It was performed on three databases (PubMed, Science Direct, and Google Scholar). Ten articles were included. RESULTS: Only two articles reported the use of CAD/CAM technologies, whereas the other eight preferred conventional registration and handmade stratification for ceramics. All indirect bonded restorations made of composite resins or ceramics had significant success rates. A temporary material was placed in most of the articles. There was no clear consensus for tissue conditioning before bonding. Depending on the authors and the articles, the follow-up period extended from 2 months to 6 years. CONCLUSIONS: The survival rate and the non-invasive procedures of indirect restorations are two main arguments that can help dental practitioners in daily practice. Development of CAD/ CAM technologies adds new perspectives in the registration, the design and production. However, more clinical trials are needed to confirm the conclusions.
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Reparação de Restauração Dentária , Hipomineralização Molar , Humanos , Resinas Compostas , Dente MolarRESUMO
BACKGROUND: Increased C-reactive protein (CRP) is used to diagnose and predict response to treatment in acute severe ulcerative colitis (UC). AIMS: To investigate the connection between CRP elevation and deep ulcers in UC. METHODS: Patients with active UC were enrolled in a multicenter prospective cohort and a retrospective cohort of consecutive patients undergoing colectomy from 2012 to 2019. RESULTS: Forty-one (9 (22%) with deep ulcers) patients were included in the prospective cohort: 4/5 (80%) patients with CRP > 100 mg/L, 2/10 (20%) patients with CRP between 30 and 100 mg/L and 3/26 (12%) patients with CRP < 30 mg/L had deep ulcers (p = 0.006). In the retrospective cohort [46 patients (31 (67%) with deep ulcers)], 14/14 (100%) patients with CRP > 100 mg/L, 11/17 (65%) patients with CRP between 30 and 100 mg/l and 6/15 (40%) patients with CRP < 30 mg/L had deep ulcers (p = 0.001). Positive predictive value of CRP > 100 mg/l for presence of deep ulcers was 80% and 100% in both cohorts, respectively. CONCLUSIONS: CRP elevation is a robust surrogate marker for presence of deep ulcers in UC. Elevated CRP or presence of deep ulcers could influence the choice of medical therapy in acute severe UC.
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Colite Ulcerativa , Humanos , Biomarcadores , Proteína C-Reativa/metabolismo , Colite Ulcerativa/complicações , Colite Ulcerativa/cirurgia , Colite Ulcerativa/diagnóstico , Estudos Prospectivos , Estudos Retrospectivos , Índice de Gravidade de Doença , ÚlceraRESUMO
KNOWLEDGE TRANSFER STATEMENT: The results of this study confirm the difficulties experienced by patients in the oral sphere. They also show that patients are able to adapt and that their demands go beyond functional rehabilitation. This work should encourage dental practitioners to be part of the overall management of the disease, involving regular checkups, preventive dental measures, and oral hygiene education. Therefore, more effective communication is required, not only between the dental and dermatological teams but also with the parents and caregivers.
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Epidermólise Bolhosa , Qualidade de Vida , Humanos , Criança , Odontólogos , Papel Profissional , Epidermólise Bolhosa/terapia , PercepçãoRESUMO
This review investigated which patterns of thyroid- and brain-related effects are seen in rats upon gestational/lactational exposure to 14 substances causing thyroid hormone imbalance by four different modes-of-action (inhibition of thyroid peroxidase, sodium-iodide symporter and deiodinase activities, enhancement of thyroid hormone clearance) or to dietary iodine deficiency. Brain-related parameters included motor activity, cognitive function, acoustic startle response, hearing function, periventricular heterotopia, electrophysiology and brain gene expression. Specific modes-of-action were not related to specific patterns of brain-related effects. Based upon the rat data reviewed, maternal serum thyroid hormone levels do not show a causal relationship with statistically significant neurodevelopmental effects. Offspring serum thyroxine together with offspring serum triiodothyronine and thyroid stimulating hormone appear relevant to predict the likelihood for neurodevelopmental effects. Based upon the collated database, thresholds of ≥60%/≥50% offspring serum thyroxine reduction and ≥20% and statistically significant offspring serum triiodothyronine reduction indicate an increased likelihood for statistically significant neurodevelopmental effects; accuracies: 83% and 67% when excluding electrophysiology (and gene expression). Measurements of brain thyroid hormone levels are likely relevant, too. The extent of substance-mediated thyroid hormone imbalance appears more important than substance mode-of-action to predict neurodevelopmental impairment in rats. Pertinent research needs were identified, e.g. to determine whether the phenomenological offspring thyroid hormone thresholds are relevant for regulatory toxicity testing. The insight from this review shall be used to suggest a tiered testing strategy to determine whether gestational/lactational substance exposure may elicit thyroid hormone imbalance and potentially also neurodevelopmental effects.
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Doenças do Sistema Endócrino , Glândula Tireoide , Gravidez , Feminino , Ratos , Animais , Tri-Iodotironina/metabolismo , Tri-Iodotironina/farmacologia , Tiroxina/metabolismo , Tiroxina/farmacologia , Lactação , Reflexo de Sobressalto , Hormônios TireóideosRESUMO
A physiologically based pharmacokinetic (PBPK) model for the important chemical phenoxyethanol (PhE) and its metabolite phenoxyacetic acid (PhAA) was built via GastroPlusTM software (version 9.0) using currently available analytically measured plasma and urinary time-courses of both PhE and its metabolite PhAA. This model was validated and used to predict tissue and urine concentrations of PhE and its metabolite PhAA in rats and humans after oral and dermal exposures. The prediction results showed that most predicted tissue concentrations of PhE or PhAA were lower than the experimental tissue concentrations based on total radioactivity. The predicted cumulative excretion of PhAA in both rats and humans fits very well with most experimental data. With this GastroPlusTM-based model, the margins of exposure (MOE) of PhE and PhAA were also calculated as 194 and 73.7, respectively. The predicted MOE of PhE is two-fold higher than the previous PBPK model built using total radioactivity-based tissue time courses, and the predicted MOE of PhAA was comparable to the previous PBPK model. These data indicate that for chemicals like PhE, GastroPlusTM can integrate multiple data sets into PBPK models to predict PK parameters for parent and metabolites in both rats and humans following intravenous, dermal, or oral exposures.
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Modelos Biológicos , Relação Quantitativa Estrutura-Atividade , Acetatos , Animais , Etilenoglicóis/farmacocinética , Humanos , RatosRESUMO
Many companies and global regulatory programs have expressed the intent to move away from in vivo animal testing to new approach methods (NAMs) as part of product safety assessments. NAMs, which include non-animal approaches for testing and assessment from computer-based modeling to in chemico or in vitro models allow faster data generation with potentially greater relevance to humans while avoiding animal use. To monitor progress implementing NAMs, each organization first must define what is in scope, starting with the definition of "animal" (e.g., mammals, vertebrates) and applicable studies (e.g., animals used for "in-house" experiments, at contract research organizations, as part of environmental monitoring). Next, organizations must establish baseline animal use, including defined rules for inclusion/ exclusion of animals that ensure consistency in future assessments. Lastly, organizations must establish metrics for animal savings based on the utility of NAM data. This paper presents one approach to establish "animal use" metrics in a toxicology program at The Dow Chemical Company. The premise of our program is that most NAM information has value for animal savings, but the value depends on how data are used (e.g., research and development, screening, or regulatory requirements) and the level of certainty for internal decision-making. This manuscript provides metrics on the impact of NAMs, allowing a quantitative assessment of animal use numbers over time, accountability for resources spent on NAM development, and identification of areas where NAM development is still needed. This approach can be refined for use at other organizations.
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Alternativas aos Testes com Animais , Benchmarking , Alérgenos , Animais , Simulação por Computador , Humanos , Medição de RiscoRESUMO
1,3 Butadiene (BD) is an industrial intermediate used primarily in product manufacturing with the greatest exposure potential via inhalation. BD was evaluated for reproductive and developmental effects in a Good Laboratory Practice (GLP)-compliant, extended OECD 421 guideline study (completed 2003). Twelve-week old rats (12/sex/dose) were exposed via whole-body inhalation to BD vapor (0, 300, 1500, 6000 ppm) for 6 h/day, 7 days/week, starting 14 days prior to mating through the day prior to euthanasia (total exposures: 83-84 days for F0 males 60-70 days for F0 females). Select F1 offspring (1/sex/litter) were dosed 7 days (postnatal days 21-27 or 28-34), then necropsied. At 1500 and 6000 ppm, treatment-related facial soiling was seen in F0 males and females with decreased body weights/gains in F0 males. F1 males and females exhibited similar effects at 1500 and 6000 ppm. Importantly, the F0 generation had no evidence of altered sperm production, testicular effects, or ovarian atrophy, which were sensitive responses in mice. The no-observed-adverse-effect-level (NOAEL) is 300 ppm due to decreased body weight/gain and facial soiling at 1500 ppm, whereas 6000 ppm serves as a NOAEL for reproductive and developmental endpoints. This study contributes to the weight-of-evidence of differential BD reproductive toxicity in rats and mice.
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Butadienos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Exposição por Inalação , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Masculino , Nível de Efeito Adverso não Observado , Ovário/efeitos dos fármacos , Ratos , Reprodução/efeitos dos fármacos , Especificidade da Espécie , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Aumento de Peso/efeitos dos fármacosRESUMO
PURPOSE: The oral care of a child with autism spectrum disorders (ASD) is a challenge, not only for dentists, but also for parents. The objective of this study was to evaluate the difficulties encountered by parents in maintaining oral hygiene in autistic children and the solutions they found to facilitate this daily act. METHODS: A questionnaire with closed and open questions about characteristics of the child and oral health at home, conducted via Google Form, was sent to French families through 301 associations of parents with autistic children. For the quantitative analysis, logistic regression was used. The open answers were analysed by theme. RESULTS: This study included 756 offspring aged 14.4 (± 8.1) years. Girls were 1.7 (95% CI: 1.1-2.8) times more likely to have toothbrushing difficulty than boys. Nonverbal patients (OR:3.2; 95% CI: 2.2-4.9), autistic patients (OR:2.8; 95% CI: 1.4-5.2), patients using pictograms (OR:1.6; 95% CI: 1.1-2.4), and younger children (OR:0.9; 95% CI: 0.9-0.9) were significantly more likely to encounter difficulties in tolerating toothbrushing. The qualitative analysis showed that parents used three main ways to facilitate toothbrushing: planning, modelling and making it enjoyable. Seventy-nine percent of parents did not feel sufficiently informed about the different oral hygiene prevention tools and techniques for their ASD children and would like to be educated in the daily management of oral hygiene. CONCLUSION: The role of parents remains essential and professionals should work in collaboration with them.
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Transtorno do Espectro Autista , Escovação Dentária , Feminino , Humanos , Masculino , Saúde Bucal , Higiene Bucal , PaisRESUMO
Background American Indian adults have a higher risk of atrial fibrillation (AF) compared with other racial groups. We implemented opportunistic screening to detect silent AF in American Indian adults attending a tribal health system using a mobile, single-lead ECG device. Methods and Results American Indian patients aged ≥50 years followed in a tribal primary care clinic with no history of AF underwent a 30-second ECG. A cardiologist overread all tracings to confirm the diagnosis of AF. After AF was confirmed, patients were referred to their primary care physician for initiation of anticoagulation. Patients seen over the same time period, who were not undergoing screening, served as controls. A total of 1019 patients received AF screening (mean age, 61.5±8.9 years, 62% women). Age and sex distribution of those screened was similar to the overall clinic population. New AF was diagnosed in 15 of 1019 (1.5%) patients screened versus 4 of 1267 (0.3%) patients who were not screened (mean difference, 1.2%; 95% CI, 0.3%-2.2%, P=0.002). Eight of 15 with new screen-detected AF were aged <65 years. Those with screen-detected AF were slightly older and had a higher CHA2DS2-VASc score than those without AF. Fourteen of 15 patients diagnosed with new AF had a CHA2DS2-VASc score ≥1 and initiated anticoagulation. Conclusions Opportunistic, mobile single-lead ECG screening for AF is feasible in tribal clinics, and detects more AF than usual care, leading to appropriate initiation of anticoagulation. AF develops at a younger age in American Indian adults who would likely benefit from earlier AF screening. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03740477.
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Indígena Americano ou Nativo do Alasca/estatística & dados numéricos , Fibrilação Atrial/etnologia , Programas de Rastreamento/métodos , Atenção Primária à Saúde/estatística & dados numéricos , Idoso , Fibrilação Atrial/diagnóstico , Eletrocardiografia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Oklahoma/epidemiologia , Prevalência , Estudos Prospectivos , Fatores de TempoRESUMO
INTRODUCTION: Pediatric dentists sometimes have to care for children who refuse to cooperate with the oral examination or dental treatment. Behavior management strategies are used, such as "tell-show-do," distraction, and positive reinforcement. Anxiety management can also be performed by the use of conscious sedation (oral premedication, nitrous oxide/oxygen inhalation). Unfortunately, these techniques are sometimes insufficient for providing oral care, and protective stabilization may be an option in some situations. Little is known on the impact of physical restraint and how practitioners feel about it. The objective of this study was to evaluate the perception of dentists using protective stabilization for dental care in children. METHODS: Semistructured qualitative interviews on the perception of pediatric dentists concerning protective stabilization were conducted in the pediatric dentistry department of the University Hospital of Toulouse, France. A thematic analysis of interview transcripts was provided via NVivo software. RESULTS: This analysis highlighted 3 main themes. First, the perceptions of dentists concerning protective stabilization showed that this procedure has a major psychological impact and led to a feeling of professional failure. Second, the reasons for which the child was stabilized were described; these concerned the child (behavior, age, number of treatments) and the environment (the parents and the medical team). Finally, we detailed how dentists manage the effects of using of protective stabilization. CONCLUSION: Dental surgeons must balance their requirement to make concrete decisions regarding the provision of care with their personal convictions about protective stabilization. This study also shows the need for specific training on this subject, as well as the desire of certain dentists that public authorities implement legislation on this matter. KNOWLEDGE TRANSFER STATEMENT: The findings of this study will improve the management of young patients by identifying situations where protective stabilization may be useful (age of the child, diagnosis, protection of the child or the medical team), while showing its psychological impact on practitioners. Finally, this work provides a basis for decision makers to propose a framework for the use of physical restraint.
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Sedação Consciente , Odontólogos , Criança , Assistência Odontológica , Humanos , Percepção , Pesquisa QualitativaRESUMO
Celiac disease (CD) is an immune-mediated systemic disorder caused by ingestion of the gluten found in wheat, rye, and barley. The currently estimated prevalence in children is about 1%. CD is a chronic enteropathy with gastrointestinal manifestations including diarrhea, abdominal distension and weight loss, but extra-intestinal features are increasingly being reported. Dental and oral manifestations such as dental enamel defects (ED), delay in dental eruption, and recurrent aphthous stomatitis (RAS) are well-recognized manifestations of CD. The aim of this study was to compare the frequency of oral manifestations (ED, RAS and delay in dental eruption) on deciduous and permanent teeth between children with CD and a control population. An oral examination was performed on 28 CD children and 59 control children. All children were younger than 12 years old and had deciduous or mixed dentition. CD children had significantly more ED and RAS than the control group (67.9% vs. 33.9% P=0.004 and 50.0% vs. 21.8% P=0.011, respectively). No delay in dental eruption was observed in CD children. ED were mainly grade I and II of Aine's classification (color defects and slight structural defects). ED were more often seen on CD children's deciduous teeth than on permanent teeth (57.1% and 13.6%, respectively; P<0.001). The main teeth affected by ED are the second molar and canines of the deciduous teeth, and the first molar, central incisor, and lateral incisors of the permanent teeth. RAS and ED that were symmetrical in all quadrants and occurred firstly in teeth that mineralize during the first year of life both seem to be signs of CD. Thus, more information for dentists and pediatricians on these oral manifestations should help improve detection of CD.
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Doença Celíaca/complicações , Estomatite Aftosa/etiologia , Doenças Dentárias/etiologia , Estudos de Casos e Controles , Doença Celíaca/diagnóstico , Criança , Pré-Escolar , Feminino , Seguimentos , França , Humanos , Lactente , Masculino , Prevalência , Estudos Prospectivos , Fatores de Risco , Estomatite Aftosa/diagnóstico , Estomatite Aftosa/epidemiologia , Doenças Dentárias/diagnóstico , Doenças Dentárias/epidemiologiaRESUMO
The European Society of Toxicologic Pathology organized an expert workshop in May 2018 to address adversity considerations related to thyroid follicular cell hypertrophy and/or hyperplasia (FCHH), which is a common finding in nonclinical toxicity studies that can have important implications for risk assessment of pharmaceuticals, food additives, and environmental chemicals. The broad goal of the workshop was to facilitate better alignment in toxicologic pathology and regulatory sciences on how to determine adversity of FCHH. Key objectives were to describe common mechanisms leading to thyroid FCHH and potential functional consequences; provide working criteria to assess adversity of FCHH in context of associated findings; and describe additional methods and experimental data that may influence adversity determinations. The workshop panel was comprised of representatives from the European Union, Japan, and the United States. Participants shared case examples illustrating issues related to adversity assessments of thyroid changes. Provided here are summary discussions, key case presentations, and panel recommendations. This information should increase consistency in the interpretation of adverse changes in the thyroid based on pathology findings in nonclinical toxicity studies, help integrate new types of biomarker data into the review process, and facilitate a more systematic approach to communicating adversity determinations in toxicology reports.
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Células Epiteliais da Tireoide , Biomarcadores , Humanos , Hiperplasia , Hipertrofia , Medição de Risco , Estados UnidosRESUMO
OBJECTIVE: The ABCB1 gene encodes P-glycoprotein (P-gp), a cellular membrane pump. One functional mutation that leads to expression of a less functional form of P-gp, ABCB1-1Δ, has been described in dogs. Individuals with this mutation can have severe adverse reactions to common veterinary pharmaceuticals that are known substrates of this pump. We investigated the detection of this mutation in samples submitted to two Australian diagnostic laboratories. METHODS: A total of 4842 dogs across 27 breeds were tested for the ABCB1-1Δ mutation from buccal swabs or EDTA blood using standard PCR, multiplex PCR, or genotyping chip. Statistical analysis was applied to determine the proportions and odds ratios of the ABCB1-1Δ mutation in herding breeds compared with non-herding breeds. RESULTS: The ABCB1-1Δ mutation was detected in nine breeds. The most commonly affected breeds were collies, Australian shepherds, white Swiss shepherds, and Shetland sheepdogs. Of 32 dogs in 18 non-herding breeds tested, one cocker spaniel and one labradoodle were positive for the mutation, both heterozygous. CONCLUSION: The most frequently affected breeds for ABCB1-1Δ mutation are the collie, Australian shepherd, white Swiss shepherd and Shetland sheepdog. As the mutation is associated with an increased incidence of adverse reactions to commonly used pharmaceuticals, veterinarians need to be aware of the breeds at most risk of carrying this mutation and consider testing these individuals prior to administering these medications.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Doenças do Cão/genética , Animais , Austrália , Cruzamento , Cães , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/veterinária , Frequência do Gene , MutaçãoRESUMO
Traditional approaches (e.g., neurobehavior, neuropathology) can detect alterations in apical endpoints indicative of developmental neurotoxicity (DNT). However, there is an increasing desire to understand mode-of-action (MOA) for DNT effects; thus, this short communication describes initial work on a neuronal differentiation assay. Basically, our laboratory used the human NT2/D1 cell line to develop an assay to evaluate toxicants for effects on all-trans retinoic acid (RA)-induced neuronal differentiation. Based on literature reports, we selected a neuronal protein, neuronal class III ß-tubulin (ß3-tubulin), as a marker of differentiation. For this assay, cultured RA-treated NT2 cells were trypsinized to individual cells, methanol fixed, and labeled with a ß3-tubulin specific monoclonal antibody (TUJ1). Characterization studies using 100,000 cells/sample showed that NT2 cells had appreciable expression of ß3-tubulin starting around day 7 of the differentiation process with a peak expression noted around day 12. Methylmercury, 22(R)-hydroxycholesterol, N-(4-hydroxyphenol)retinamide (4HPR), and 9-cis retinoic acid were selected as initial test compounds. Of these, only 9-cis RA, which is known to affect the RA pathway, was positive for specific impacts on differentiation. These results demonstrate the feasibility of using a flow cytometry method targeting specific cellular biomarkers for evaluating effects on neuronal differentiation. Additional assays are needed to detect compounds targeting other (non-RA) neuronal differentiation pathways. Ultimately, a battery of in vitro assays would be needed to evaluate the potential MOAs involved in altered neuronal differentiation.
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Alitretinoína/toxicidade , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Testes de Toxicidade , Tretinoína/farmacologia , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fenretinida/toxicidade , Citometria de Fluxo , Humanos , Hidroxicolesteróis/toxicidade , Compostos de Metilmercúrio/toxicidade , Neurônios/metabolismo , Neurônios/patologia , Medição de Risco , Transdução de Sinais , Fatores de Tempo , Tubulina (Proteína)/metabolismoRESUMO
Thyroid hormones (THs; T3 and T4) play a role in development of cardiovascular, reproductive, immune and nervous systems. Thus, interpretation of TH changes from rodent studies (during pregnancy, in fetuses, neonates, and adults) is critical in hazard characterization and risk assessment. A roundtable session at the 2017 Society of Toxicology (SOT) meeting brought together academic, industry and government scientists to share knowledge and different perspectives on technical and data interpretation issues. Data from a limited group of laboratories were compiled for technical discussions on TH measurements, including good practices for reliable serum TH data. Inter-laboratory historical control data, derived from immunoassays or mass spectrometry methods, revealed: 1) assay sensitivities vary within and across methodologies; 2) TH variability is similar across animal ages; 3) laboratories generally achieve sufficiently sensitive TH quantitation levels, although issues remain for lower levels of serum TH and TSH in fetuses and postnatal day 4 pups; thus, assay sensitivity is critical at these life stages. Best practices require detailed validation of rat serum TH measurements across ages to establish assay sensitivity and precision, and identify potential matrix effects. Finally, issues related to data interpretation for biological understanding and risk assessment were discussed, but their resolution remains elusive.
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Glândula Tireoide/efeitos dos fármacos , Tiroxina/efeitos adversos , Tri-Iodotironina/efeitos adversos , Animais , Humanos , Imunoensaio , Espectrometria de Massas , Medição de Risco , Tiroxina/administração & dosagem , Tri-Iodotironina/administração & dosagemRESUMO
Developmental neurotoxicity (DNT) is an important endpoint for the safety assessment of chemicals. However, the current in vivo animal model for DNT assessment is resource-intensive and may not fully capture all mechanisms that may be relevant to DNT in humans. As a result, there is a growing need for more reliable, time- and cost-efficient approaches for DNT evaluation. Toward this end, many stem/progenitor cell-based in vitro models and alternative organism-based models are becoming available with the potential for high throughput screening of DNT. Meanwhile, with advances in the knowledgebase of DNT molecular mechanisms and the identification of DNT-related adverse outcome pathways (AOP) there is potential to develop a mechanism-based integrated testing strategy for DNT assessment. This review summarizes the state of science regarding currently available human stem/progenitor cell-based in vitro models and alternative organism-based models that could be used for DNT testing. In addition, the current knowledge regarding DNT AOPs is reviewed to identify common key events that could serve as critical endpoints to assess multiple AOPs that underlie DNT. Following the identification of common key events, a streamlined strategy is proposed using alternative models to assess the DNT potential of chemicals as an early screening approach for chemicals in development.
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Alternativas aos Testes com Animais , Encéfalo/efeitos dos fármacos , Desenvolvimento de Medicamentos/métodos , Ensaios de Triagem em Larga Escala , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Testes de Toxicidade , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Humanos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/fisiopatologia , Reprodutibilidade dos Testes , Medição de RiscoRESUMO
GOALS: The goal of this study was to evaluate the influence of defecation postural modification devices (DPMDs) on normal bowel patterns. BACKGROUND: The introduction of DPMDs has brought increased awareness to bowel habits in western populations. MATERIALS AND METHODS: A prospective crossover study of volunteers was performed that included real-time collection of data regarding bowel movements (BMs) for 4 weeks (first 2 wk without DPMD and subsequent 2 wk with DPMD). Primary outcomes of interest included BM duration, straining, and bowel emptiness with and without DPMD use. RESULTS: In total, 52 participants (mean age, 29 y and 40.1% female) were recruited for this study. At baseline 15 subjects (28.8%) reported incomplete emptying, 23 subjects (44.2%) had increased straining, and 29 subjects (55.8%) noticed blood on their toilet paper in the past year. A total of 1119 BMs were recorded (735 without DPMD and 384 with DPMD). Utilizing the DPMD resulted in increased bowel emptiness (odds ratio, 3.64; 95% confidence interval (CI), 2.78-4.77) and reduced straining patterns (odds ratio, 0.23; 95% CI, 0.18-0.30). Moreover, without the DPMD, participants had an increase in BM duration (fold increase, 1.25; 95% CI, 1.17-1.33). CONCLUSIONS: DPMDs positively influenced BM duration, straining patterns, and complete evacuation of bowels in this study.
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Aparelho Sanitário , Defecação/fisiologia , Adulto , Estudos Cross-Over , Desenho de Equipamento , Feminino , Voluntários Saudáveis , Humanos , Masculino , Postura , Estudos ProspectivosRESUMO
The endocrine system is responsible for growth, development, maintaining homeostasis and for the control of many physiological processes. Due to the integral nature of its signaling pathways, it can be difficult to distinguish endocrine-mediated adverse effects from transient fluctuations, adaptive/compensatory responses, or adverse effects on the endocrine system that are caused by mechanisms outside the endocrine system. This is particularly true in toxicological studies that require generation of effects through the use of Maximum Tolerated Doses (or Concentrations). Endocrine-mediated adverse effects are those that occur as a consequence of the interaction of a chemical with a specific molecular component of the endocrine system, for example, a hormone receptor. Non-endocrine-mediated adverse effects on the endocrine system are those that occur by other mechanisms. For example, systemic toxicity, which perturbs homeostasis and affects the general well-being of an organism, can affect endocrine signaling. Some organs/tissues can be affected by both endocrine and non-endocrine signals, which must be distinguished. This paper examines in vitro and in vivo endocrine endpoints that can be altered by non-endocrine processes. It recommends an evaluation of these issues in the assessment of effects for the determination of endocrine disrupting properties of chemicals. This underscores the importance of using a formal weight of evidence (WoE) process to evaluate potential endocrine activity.
Assuntos
Disruptores Endócrinos/farmacologia , Disruptores Endócrinos/uso terapêutico , Sistema Endócrino/diagnóstico por imagem , Animais , Humanos , Medição de RiscoRESUMO
CONTEXT: The recent recommendations of the European Endocrine Society states that the performance of computed tomography (CT) to characterize 'true' adrenal incidentalomas (AIs) remains debatable. OBJECTIVE: To determine relevant thresholds for usual CT parameters for the diagnosis of benign tumors using robust reference standard among a large series of 'true' AIs recruited in an endocrinological setting. DESIGN: Retrospective study of 253 AIs in 233 consecutive patients explored in a single university hospital: 183 adenomas, 33 pheochromocytomas, 23 adrenocortical carcinomas, 5 other malignant tumors and 9 other benign tumors. Reference standard was histopathology in 118 AIs, biological diagnosis of pheochromocytoma in 2 AIs and size stability after at least 1 year of follow-up in 133 AIs. METHODS: Sensitivity, specificity and positive and negative predictive values were estimated for various thresholds of size, unenhanced attenuation (UA), relative and absolute wash-out (RPW, APW) of contrast media. 197 scans were reviewed independently in a blinded fashion by two expert radiologists to assess inter-observer reproducibility of measurements. RESULTS: Criteria associated with a 100% positive predictive value for the diagnosis of benign AI were: a combination of size and UA: 30 mm and 20 HU or 40 mm and 15 HU, respectively; RPW >53%; and APW >78%. Non-adenomatous AIs with rapid contrast wash-out were exclusively benign pseudocysts and pheochromocytomas, suggesting that classical thresholds of 60% and 40% for APW and RPW, respectively, can be safely used for patients with normal metanephrine values. Inter-observer reproducibility of all parameters was excellent (intra-class correlation coefficients: 0.96-0.99). CONCLUSIONS: Our study, the largest conducted in AIs recruited in an endocrinological setting, suggests safe thresholds for quantitative CT parameters to avoid false diagnoses of benignity.