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Prediction of hepatic clearance of drugs (via uptake or metabolism) from in vitro systems continues to be problematic, particularly when plasma protein binding is high. The following work explores simultaneous assessment of both clearance processes, focusing on a commercial hepatocyte-fibroblast co-culture system (HµREL) over a 24-hour period using six probe drugs (ranging in metabolic and transporter clearance and low-to-high plasma protein binding). A rat hepatocyte co-culture assay was established using drug depletion (measuring both medium and total concentrations) and cell uptake kinetic analysis, both in the presence and absence of plasma protein (1% bovine serum albumin). Secretion of endogenous albumin was monitored as a marker of viability, and this reached 0.004% in incubations (at a rate similar to in vivo synthesis). Binding to stromal cells was substantial and required appropriate correction factors. Drug concentration-time courses were analyzed both by conventional methods and a mechanistic cell model prior to in vivo extrapolation. Clearance assayed by drug depletion in conventional suspended rat hepatocytes provided a benchmark to evaluate co-culture value. Addition of albumin appeared to improve predictions for some compounds (where fraction unbound in the medium is less than 0.1); however, for high-binding drugs, albumin significantly limited quantification and thus predictions. Overall, these results highlight ongoing challenges concerning in vitro hepatocyte system complexity and limitations of practical expediency. Considering this, more reliable measurement of hepatically cleared compounds seems possible through judicious use of available hepatocyte systems, including co-culture systems, as described herein; this would include those compounds with low metabolic turnover but high active uptake clearance. SIGNIFICANCE STATEMENT: Co-culture systems offer a more advanced tool than standard hepatocytes, with the ability to be cultured for longer periods of time, yet their potential as an in vitro tool has not been extensively assessed. We evaluate the strengths and limitations of the HµREL system using six drugs representing various metabolic and transporter-mediated clearance pathways with various degrees of albumin binding. Studies in the presence/absence of albumin allow in vitro-in vivo extrapolation and a framework to maximize their utility.
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Underestimation of aldehyde oxidase (AO)-mediated clearance by current in vitro assays leads to uncertainty in human dose projections, thereby reducing the likelihood of success in drug development. In the present study we first evaluated the current drug development practices for AO substrates. Next, the overall predictive performance of in vitro-in vivo extrapolation of unbound hepatic intrinsic clearance (CLint,u) and unbound hepatic intrinsic clearance by AO (CLint,u,AO) was assessed using a comprehensive literature database of in vitro (human cytosol/S9/hepatocytes) and in vivo (intravenous/oral) data collated for 22 AO substrates (total of 100 datapoints from multiple studies). Correction for unbound fraction in the incubation was done by experimental data or in silico predictions. The fraction metabolized by AO (fmAO) determined via in vitro/in vivo approaches was found to be highly variable. The geometric mean fold errors (gmfe) for scaled CLint,u (mL/min/kg) were 10.4 for human hepatocytes, 5.6 for human liver cytosols, and 5.0 for human liver S9, respectively. Application of these gmfe's as empirical scaling factors improved predictions (45%-57% within twofold of observed) compared with no correction (11%-27% within twofold), with the scaling factors qualified by leave-one-out cross-validation. A road map for quantitative translation was then proposed following a critical evaluation on the in vitro and clinical methodology to estimate in vivo fmAO In conclusion, the study provides the most robust system-specific empirical scaling factors to date as a pragmatic approach for the prediction of in vivo CLint,u,AO in the early stages of drug development. SIGNIFICANCE STATEMENT: Confidence remains low when predicting in vivo clearance of AO substrates using in vitro systems, leading to de-prioritization of AO substrates from the drug development pipeline to mitigate risk of unexpected and costly in vivo impact. The current study establishes a set of empirical scaling factors as a pragmatic tool to improve predictability of in vivo AO clearance. Developing clinical pharmacology strategies for AO substrates by utilizing mass balance/clinical drug-drug interaction data will help build confidence in fmAO.
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Aldehído Oxidasa , Hígado , Humanos , Aldehído Oxidasa/metabolismo , Tasa de Depuración Metabólica , Hígado/metabolismo , Hepatocitos/metabolismo , Microsomas Hepáticos/metabolismoRESUMEN
The kinetics of metabolism of deltamethrin (DLM) and cis- and trans-permethrin (CPM and TPM) was studied in male Sprague-Dawley rat and human liver microsomes. DLM metabolism kinetics was also studied in isolated rat hepatocytes, liver microsomes and cytosol. Apparent intrinsic clearance (CLint) values for the metabolism of DLM, CPM and TPM by cytochrome P450 (CYP) and carboxylesterase (CES) enzymes in rat and human liver microsomes decreased with increasing microsomal protein concentration. However, when apparent CLint values were corrected for nonspecific binding to allow calculation of unbound (i.e., corrected) CLint values, the unbound values did not vary greatly with microsomal protein concentration. Unbound CLint values for metabolism of 0.05-1 µM DLM in rat liver microsomes (CYP and CES enzymes) and cytosol (CES enzymes) were not significantly different from rates of DLM metabolism in isolated rat hepatocytes. This study demonstrates that the nonspecific binding of these highly lipophilic compounds needs to be taken into account in order to obtain accurate estimates of rates of in vitro metabolism of these pyrethroids. While DLM is rapidly metabolised in vitro, the hepatocyte membrane does not appear to represent a barrier to the absorption and hence subsequent hepatic metabolism of this pyrethroid.
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Citosol/metabolismo , Hígado/metabolismo , Permetrina/metabolismo , Animales , Carboxilesterasa/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Hepatocitos/metabolismo , Humanos , Cinética , Masculino , Microsomas Hepáticos/metabolismo , Nitrilos/metabolismo , Piretrinas/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Hazard and disaster research requires a willingness to step outside of traditional disciplinary ontological and epistemological assumptions to both accommodate and integrate different perspectives. Moreover, the complex qualities of hazards and disasters necessitate interdisciplinary approaches to inform theory development that encompasses environmental, human, and infrastructure systems at multiple scales and units of analysis. Unfortunately, truly integrative hazard and disaster theory at a scale broad enough to account for the many systems and processes involved is currently limited. In this article, we argue that robust hazard and disaster theory can only arise from interdisciplinary research and collaboration. We examine challenges to the development of interdisciplinary hazard and disaster theory, and discuss the characteristics of theory necessary for the goal-oriented nature of research aimed at reducing disaster impact.
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Disasters occur at the intersections of social, natural, and built environments, and robust understanding of these interactions can only occur through insight generated from different disciplines. Yet, there are cultural, epistemological, and methodological differences across the many disciplines concerned with hazards and disasters that can make conducting interdisciplinary research difficult. Approaches are needed to overcome these challenges. This article argues that interdisciplinary disaster research can be successful when it entails an iterative process in which researchers from different disciplines work collaboratively and exert reciprocal influence to generate disaster systems knowledge. Disaster systems knowledge is interdisciplinary and is defined as a comprehensive understanding of the intersections of built, natural, and human environmental factors and their interplay in hazards and disasters. The iterative process can reduce disciplinary biases and privileges by encouraging collaboration among researchers to help ensure disciplinary knowledge complements other disciplinary knowledge, to ultimately generate interdisciplinary disaster systems knowledge. The article concludes by illustrating the process by analyzing a research case study of an interdisciplinary approach to volcanic risk reduction.
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Given the increasing threat of disasters in the United States and elsewhere around the world, well-tested assessment tools that operationalise specific protective factors associated with adaptation and resilience to such events are needed. Consequently, the authors proposed, developed, and validated the Disaster Adaptation and Resilience Scale (DARS) to measure five domains found to support adaptive responses in individuals exposed to disasters: physical resources; social resources; problem-solving; distress regulation; and optimism. The development and validation processes of DARS occurred across two studies: the first comprised construct development, item generation, and expert review, whereas the second involved a full validation evaluation of the psychometric properties of the scale in a sample of adults exposed to a disaster in the US (N=625). The results revealed that DARS had psychometric properties that support its use among adults experiencing a disaster. A discussion is presented on how the scale can be employed in both research and practice.
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Desastres , Adulto , HumanosRESUMEN
Information and communication resources are needed for individuals to cope with a public health emergency like the COVID-19 pandemic. These resources include interpersonal, organizational, and mediated communication, which collectively constitute a communication ecology. This interdisciplinary special issue of American Behavioral Scientist focuses on applications of a communication ecology perspective to the COVID-19 pandemic. Each article in this issue examines one or more specific aspect of COVID-19 communication ecologies to expand understanding of how a variety of communication resources can foster individual and collective coping with a global public health crisis. Insights from this issue can inform ongoing response to COVID-19 and planning for future public health crises.
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In the present study, the beagle dog was evaluated as a preclinical model to investigate organic anion transporting polypeptide (OATP)-mediated hepatic clearance. In vitro studies were performed with nine OATP substrates in three lots of plated male dog hepatocytes ± OATP inhibitor cocktail to determine total uptake clearance (CLuptake) and total and unbound cell-to-medium concentration ratio (Kpuu). In vivo intrinsic hepatic clearances (CLint,H) were determined following intravenous drug administration (0.1 mg/kg) in male beagle dogs. The in vitro parameters were compared with those previously reported in plated human, monkey, and rat hepatocytes; the ability of cross-species scaling factors to improve prediction of human in vivo clearance was assessed. CLuptake in dog hepatocytes ranged from 9.4 to 135 µl/min/106 cells for fexofenadine and telmisartan, respectively. Active process contributed >75% to CLuptake for 5/9 drugs. Rosuvastatin and valsartan showed Kpuu > 10, whereas cerivastatin, pitavastatin, repaglinide, and telmisartan had Kpuu < 5. The extent of hepatocellular binding in dog was consistent with other preclinical species and humans. The bias (2.73-fold) obtained from comparison of predicted versus in vivo dog CLint,H was applied as an average empirical scaling factor (ESFav) for in vitro-in vivo extrapolation of human CLint,H The ESFav based on dog reduced underprediction of human CLint,H for the same data set (geometric mean fold error = 2.1), highlighting its utility as a preclinical model to investigate OATP-mediated uptake. The ESFav from all preclinical species resulted in comparable improvement of human clearance prediction, in contrast to drug-specific empirical scalars, rationalized by species differences in expression and/or relative contribution of particular transporters to drug hepatic uptake.
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Evaluación Preclínica de Medicamentos/métodos , Tasa de Depuración Metabólica , Transportadores de Anión Orgánico/metabolismo , Preparaciones Farmacéuticas/metabolismo , Especificidad de la Especie , Animales , Perros , Hepatocitos/metabolismo , Humanos , Infusiones Intravenosas , Hígado/citología , Hígado/metabolismo , Masculino , Modelos Animales , Modelos Biológicos , Preparaciones Farmacéuticas/administración & dosificaciónRESUMEN
Disaster survivors may experience a range of mental health reactions that can include posttraumatic stress (PTS) and posttraumatic growth (PTG). The current study examines the associations between citizen disaster communication, PTS, and PTG among individuals in North Carolina communities impacted by Hurricane Matthew, approximately six weeks following the event. Participants who communicated more frequently following the hurricane exhibited more PTS and PTG. Communication activities focused on connecting with loved ones and cognitively restructuring the disaster experience were associated with PTS and PTG, whereas communication activities confirming disaster reports and assisting with disaster recovery were associated solely with PTG. Results illustrate the need for robust disaster communication ecologies to facilitate public disaster mental health response and coordination.
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Comunicación , Tormentas Ciclónicas , Desastres , Crecimiento Psicológico Postraumático , Trastornos por Estrés Postraumático/epidemiología , Sobrevivientes/psicología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , North Carolina/epidemiología , Sobrevivientes/estadística & datos numéricosRESUMEN
Natural and human-caused disasters pose a significant risk to the health and well-being of people. Journalists and news organisations can fulfil multiple roles related to disasters, ranging from providing warnings, assessing disaster mitigation and preparedness, and reporting on what occurs, to aiding long-term recovery and fostering disaster resilience. This paper considers these possible functions of disaster journalism and draws on semi-structured interviews with 24 journalists in the United States to understand better their approach to the discipline. A thematic analysis was employed, which resulted in the identification of five main themes and accompanying subthemes: (i) examining disaster mitigation and preparedness; (ii) facilitating recovery; (iii) self-care and care of journalists; (iv) continued spread of social media; and (v) disaster journalism ethics. The paper concludes that disaster journalism done poorly can result in harm, but done well, it can be an essential instrument with respect to public disaster planning, management, response, and recovery.
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Planificación en Desastres/organización & administración , Desastres , Periodismo , Humanos , Investigación Cualitativa , Estados UnidosRESUMEN
Hepatic organic anion-transporting polypeptides (OATP) 1B1 and 1B3 are clinically relevant transporters associated with significant drug-drug interactions (DDIs) and safety concerns. Given that OATP1Bs in cynomolgus monkey share >90% degree of gene and amino acid sequence homology with human orthologs, we evaluated the in vitro-in vivo translation of OATP1B-mediated DDI risk using this preclinical model. In vitro studies using plated cynomolgus monkey hepatocytes showed active uptake Km values of 2.0 and 3.9 µM for OATP1B probe substrates, pitavastatin and rosuvastatin, respectively. Rifampicin inhibited pitavastatin and rosuvastatin active uptake in monkey hepatocytes with IC50 values of 3.0 and 0.54 µM, respectively, following preincubation with the inhibitor. Intravenous pharmacokinetics of 2H4-pitavastatin and 2H6-rosuvastatin (0.2 mg/kg) and the oral pharmacokinetics of cold probes (2 mg/kg) were studied in cynomolgus monkeys (n = 4) without or with coadministration of single oral ascending doses of rifampicin (1, 3, 10, and 30 mg/kg). A rifampicin dose-dependent reduction in i.v. clearance of statins was observed. Additionally, oral pitavastatin and rosuvastatin plasma exposure increased up to 19- and 15-fold at the highest dose of rifampicin, respectively. Use of in vitro IC50 obtained following 1 hour preincubation with rifampicin (0.54 µM) predicted correctly the change in mean i.v. clearance and oral exposure of statins as a function of mean unbound maximum plasma concentration of rifampicin. This study demonstrates quantitative translation of in vitro OATP1B IC50 to predict DDIs using cynomolgus monkey as a preclinical model and provides further confidence in application of in vitro hepatocyte data for the prediction of clinical OATP1B-mediated DDIs.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Quinolinas/farmacología , Rosuvastatina Cálcica/farmacología , Administración Oral , Animales , Transporte Biológico , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Células HEK293 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Macaca fascicularis , Masculino , Quinolinas/administración & dosificación , Quinolinas/metabolismo , Quinolinas/farmacocinética , Rosuvastatina Cálcica/administración & dosificación , Rosuvastatina Cálcica/metabolismo , Rosuvastatina Cálcica/farmacocinética , Distribución TisularRESUMEN
Prediction of clearance-a vital component of drug discovery-remains in need of improvement and, in particular, requires more incisive assessment of mechanistic methodology in vitro, according to a number of recent reports. Although isolated hepatocytes have become an irreplaceable standard system for the measurement of intrinsic hepatic clearance mediated by active uptake transport and metabolism, the lack of prediction reliability appears to reflect a lack of methodological validation, especially for highly cleared drugs, as we have previously shown. Here, novel approaches were employed to explore fundamental experimental processes and associated potential limitations of in vitro predictions of clearance. Rat hepatocytes deemed nonviable by trypan blue staining showed undiminished metabolic activity for probe cytochrome P450 (P450) substrates midazolam and propranolol; supplementation with NADPH enhanced these activities. Extensive permeabilization of the plasma membrane using saponin showed either full or minimal P450 activity, depending on the presence or absence of 1 mM NADPH, respectively. The shaking of incubations facilitated P450 metabolic rates up to 5-fold greater than static incubation, depending on intrinsic clearance, indicating the critical influence of the unstirred water layer (UWL). Permeabilization allowed static incubation metabolic rates to approach those of shaking for intact cells, indicating an artificially induced breakdown of the UWL. Permeabilization combined with shaking allowed an increased metabolic rate for saquinavir, resolving the membrane permeability limitation for this drug. These findings advance the interpretation of the rate-limiting processes involved in intrinsic clearance measurements and could be critical for successful in vitro prediction.
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Permeabilidad de la Membrana Celular/fisiología , Hepatocitos/metabolismo , Hígado/metabolismo , Tasa de Depuración Metabólica/fisiología , Agua/metabolismo , Animales , Transporte Biológico/fisiología , Sistema Enzimático del Citocromo P-450/metabolismo , Cinética , Masculino , Midazolam/metabolismo , NADP/metabolismo , Propranolol/metabolismo , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Saquinavir/metabolismoRESUMEN
Hepatocyte drug depletion-time assays are well established for determination of metabolic clearance in vitro. The present study focuses on the refinement and evaluation of a "media loss" assay, an adaptation of the conventional depletion assay involving centrifugation of hepatocytes prior to sampling, allowing estimation of uptake in addition to metabolism. Using experimental procedures consistent with a high throughput, a selection of 12 compounds with a range of uptake and metabolism characteristics (atorvastatin, cerivastatin, clarithromycin, erythromycin, indinavir, pitavastatin, repaglinide, rosuvastatin, saquinavir, and valsartan, with two control compounds-midazolam and tolbutamide) were investigated in the presence and absence of the cytochrome P450 inhibitor 1-aminobenzotriazole and organic anion transporter protein inhibitor rifamycin SV in rat hepatocytes. Data were generated simultaneously for a given drug, and provided, through the use of a mechanistic cell model, clearance terms characterizing metabolism, active and passive uptake, together with intracellular binding and partitioning parameters. Results were largely consistent with the particular drug characteristics, with active uptake, passive diffusion, and metabolic clearances ranging between 0.4 and 777, 3 and 383, and 2 and 236 µl/min per milligram protein, respectively. The same experiments provided total and unbound drug cellular partition coefficients ranging between 3.8 and 254 and 2.3 and 8.3, respectively, and intracellular unbound fractions between 0.014 and 0.263. Following in vitro-in vivo extrapolation, the lowest prediction bias was noted using uptake clearance, compared with metabolic clearance or apparent clearance from the media loss assay alone. This approach allows rapid and comprehensive characterization of hepatocyte drug disposition valuable for prediction of hepatic processes in vivo.
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Hígado/metabolismo , Preparaciones Farmacéuticas/metabolismo , Animales , Transporte Biológico/fisiología , Hepatocitos/metabolismo , Inactivación Metabólica/fisiología , Masculino , Tasa de Depuración Metabólica/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
This work explores the utility of the cynomolgus monkey as a preclinical model to predict hepatic uptake clearance mediated by organic anion transporting polypeptide (OATP) transporters. Nine OATP substrates (rosuvastatin, pravastatin, repaglinide, fexofenadine, cerivastatin, telmisartan, pitavastatin, bosentan, and valsartan) were investigated in plated cynomolgus monkey and human hepatocytes. Total uptake clearance and passive diffusion were measured in vitro from initial rates in the absence and presence of the OATP inhibitor rifamycin SV , respectively. Total uptake clearance values in plated hepatocytes ranged over three orders of magnitude in both species, with a similar rank order and good agreement in the relative contribution of active transport to total uptake between cynomolgus monkey and human. In vivo hepatic clearance for these nine drugs was determined in cynomolgus monkey after intravenous dosing. Hepatic clearances showed a range similar to human parameters and good predictions from respective hepatocyte parameters (with 2.7- and 3.8-fold bias on average, respectively). The use of cross-species empirical scaling factors (determined from cynomolgus monkey data either as the data set average or individual drug values) improved prediction (less bias, better concordance) of human hepatic clearance from human hepatocyte data alone. In vitro intracellular binding in hepatocytes also correlated well between species. It is concluded that the minimal species differences observed for the current data set between cynomolgus monkey and human hepatocyte uptake, both in vitro and in vivo, support future use of this preclinical model to delineate drug hepatic uptake and enable prediction of human in vivo intrinsic hepatic clearance.
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Hepatocitos/metabolismo , Hígado/metabolismo , Tasa de Depuración Metabólica/fisiología , Transportadores de Anión Orgánico/metabolismo , Preparaciones Farmacéuticas/metabolismo , Adulto , Animales , Transporte Biológico/fisiología , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/metabolismo , Cinética , Macaca fascicularis , Péptidos/metabolismoRESUMEN
Accumulation of respiratory drugs in human alveolar macrophages (AMs) has not been extensively studied in vitro and in silico despite its potential impact on therapeutic efficacy and/or occurrence of phospholipidosis. The current study aims to characterize the accumulation and subcellular distribution of drugs with respiratory indication in human AMs and to develop an in silico mechanistic AM model to predict lysosomal accumulation of investigated drugs. The data set included 9 drugs previously investigated in rat AM cell line NR8383. Cell-to-unbound medium concentration ratio (Kp,cell) of all drugs (5 µM) was determined to assess the magnitude of intracellular accumulation. The extent of lysosomal sequestration in freshly isolated human AMs from multiple donors (n = 5) was investigated for clarithromycin and imipramine (positive control) using an indirect in vitro method (±20 mM ammonium chloride, NH4Cl). The AM cell parameters and drug physicochemical data were collated to develop an in silico mechanistic AM model. Three in silico models differing in their description of drug membrane partitioning were evaluated; model (1) relied on octanol-water partitioning of drugs, model (2) used in vitro data to account for this process, and model (3) predicted membrane partitioning by incorporating AM phospholipid fractions. In vitro Kp,cell ranged >200-fold for respiratory drugs, with the highest accumulation seen for clarithromycin. A good agreement in Kp,cell was observed between human AMs and NR8383 (2.45-fold bias), highlighting NR8383 as a potentially useful in vitro surrogate tool to characterize drug accumulation in AMs. The mean Kp,cell of clarithromycin (81, CV = 51%) and imipramine (963, CV = 54%) were reduced in the presence of NH4Cl by up to 67% and 81%, respectively, suggesting substantial contribution of lysosomal sequestration and intracellular binding in the accumulation of these drugs in human AMs. The in vitro data showed variability in drug accumulation between individual human AM donors due to possible differences in lysosomal abundance, volume, and phospholipid content, which may have important clinical implications. Consideration of drug-acidic phospholipid interactions significantly improved the performance of the in silico models; use of in vitro Kp,cell obtained in the presence of NH4Cl as a surrogate for membrane partitioning (model (2)) captured the variability in clarithromycin and imipramine Kp,cell observed in vitro and showed the best ability to predict correctly positive and negative lysosomotropic properties. The developed mechanistic AM model represents a useful in silico tool to predict lysosomal and cellular drug concentrations based on drug physicochemical data and system specific properties, with potential application to other cell types.
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Lisosomas/metabolismo , Macrófagos Alveolares/metabolismo , Preparaciones Farmacéuticas/administración & dosificación , Anciano , Animales , Línea Celular , Claritromicina/administración & dosificación , Simulación por Computador , Femenino , Humanos , Imipramina/administración & dosificación , Macrófagos Alveolares/efectos de los fármacos , Masculino , Persona de Mediana Edad , Fosfolípidos/metabolismo , Ratas , Distribución TisularRESUMEN
Children have been identified as particularly vulnerable to psychological and behavioral difficulties following disaster. Public child and family disaster communication is one public health tool that can be utilized to promote coping/resilience and ameliorate maladaptive child reactions following an event. We conducted a review of the public disaster communication literature and identified three main functions of child and family disaster communication: fostering preparedness, providing psychoeducation, and conducting outreach. Our review also indicates that schools are a promising system for child and family disaster communication. We complete our review with three conclusions. First, theoretically, there appears to be a great opportunity for public disaster communication focused on child disaster reactions. Second, empirical research assessing the effects of public child and family disaster communication is essentially nonexistent. Third, despite the lack of empirical evidence in this area, there is opportunity for public child and family disaster communication efforts that address new domains.
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Adaptación Psicológica , Desastres , Trastornos Mentales/prevención & control , Salud Mental , Instituciones Académicas , Niño , Relaciones Comunidad-Institución , Humanos , Difusión de la Información , Trastornos Mentales/etiología , Salud PúblicaRESUMEN
The literature on children's responses to disasters is well developed with increasing attention to the confounding experiences of displacement. This paper presents an overview of the emotional and behavioral effects of displacement on children and adolescents and describes their educational adjustment in terms of both academic achievement and school behavior. A summary of family effects elucidates how children's functioning is influenced through the family system in which they are embedded. The psychosocial impact of displacement reflects the myriad social losses that children and their families may face. Information from this review of the current literature on the effects of displacement may inform the design and delivery of support and intervention services for children and families following disasters.
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Logro , Conducta del Adolescente/psicología , Conducta Infantil/psicología , Desastres , Refugiados/psicología , Estudiantes/psicología , Adolescente , Niño , Escolaridad , Ajuste Emocional , Familia/psicología , Humanos , Refugiados/estadística & datos numéricos , Estudiantes/estadística & datos numéricosRESUMEN
OBJECTIVE: This study explored the effects of media coverage of a terrorist incident in individuals remote from the location of a major attack who had directly experienced a prior terrorist incident. METHOD: Directly-exposed survivors of the 1995 Oklahoma City bombing, initially studied six months after the incident, and indirectly-affected Oklahoma City community residents were assessed two to seven months after the September 11, 2001, attacks. Survivors were assessed for a diagnosis of bombing-related posttraumatic stress disorder (PTSD) at index and follow up, and emotional reactions and September 11 media behavior were assessed in all participants. RESULTS: Among the three investigated forms of media (television, radio, and newspaper), only television viewing was associated with 9/11-related posttraumatic stress reactions. Exposure to the Oklahoma City bombing was associated with greater arousal in relation to the September 11 attacks, and among survivors, having developed bombing-related PTSD was associated with higher scores on all three September 11 posttraumatic stress response clusters (intrusion, avoidance, and arousal). Although time spent watching television coverage of the September 11 attacks and fear-related discontinuation of media contact were not associated with Oklahoma City bombing exposure, discontinuing September 11 media contact due to fear was associated with avoidance/numbing in the full sample and in the analysis restricted to the bombing survivors. CONCLUSION: Surviving a prior terrorist incident and developing PTSD in relation to that incident may predispose individuals to adverse reactions to media coverage of a future terrorist attack.
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Miedo , Trastornos por Estrés Postraumático/psicología , Sobrevivientes/psicología , Terrorismo/psicología , Bombas (Dispositivos Explosivos) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oklahoma , Conducta Social , Adulto JovenRESUMEN
Posttraumatic stress disorder (PTSD) is a mental health disorder that occurs for some individuals following a traumatic experience and that can cause significant health, mental health, and functioning problems. The concept of PTSD has multiple components (cause, reactions, and treatment), which provides for great variety in the experience of an individual with PTSD. Given this complexity, the news media's construction of PTSD is likely an important influence in determining how the public understands PTSD, but research has yet to investigate how the news media depict PTSD. This study addresses that gap in the literature by examining New York Times coverage of PTSD from 1950 to 2012. Results indicate that the number of PTSD articles during this time period increased, with coverage spikes related to U.S. military conflicts and the September 11, 2001, terrorist attacks. Almost half (49.14%) of all PTSD articles included military service as a PTSD cause. Military PTSD articles were more likely than civilian PTSD articles to depict the disorder as causing anger/irritability/rage, homicide/violence/rape, suicide, substance abuse, and home/work/relationship problems. PTSD news stories were almost always (94.8%) situated in the current time and most frequently (46.6%) used a community frame. Implications for public understanding of PTSD are discussed.
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Periódicos como Asunto/estadística & datos numéricos , Trastornos por Estrés Postraumático , Conflictos Armados , Humanos , Personal Militar/psicología , Opinión Pública , Ataques Terroristas del 11 de Septiembre , Trastornos por Estrés Postraumático/psicologíaRESUMEN
PURPOSE: To assess accumulation and lysosomal sequestration of 9 drugs used in respiratory indications (plus imipramine as positive control) in the alveolar macrophage (AM) cell line NR8383. METHODS: For all drugs, uptake at 5 µM was investigated at 37 and 4°C to delineate active uptake and passive diffusion processes. Accumulation of basic clarithromycin, formoterol and imipramine was also assessed over 0.1-100 µM concentration range. Lysosomal sequestration was investigated using ammonium chloride (NH4Cl), monensin and nigericin. Impact of lysosomal sequestration on clarithromycin accumulation kinetics was investigated. RESULTS: Both cell-to-medium concentration ratio (Kp) and uptake clearance (CLuptake) ranged > 400-fold for the drugs investigated. The greatest Kp was observed for imipramine (391) and clarithromycin (82), in contrast to no accumulation seen for terbutaline. A concentration-dependent accumulation was evident for the basic drugs investigated. Imipramine and clarithromycin Kp and CLuptake were reduced by 59-85% in the presence of NH4Cl and monensin/nigericin, indicating lysosomal accumulation, whereas lysosomal sequestration was not pronounced for the other 8 respiratory drugs. Clarithromycin uptake rate was altered by NH4Cl, highlighting the impact of subcellular distribution on accumulation kinetics. CONCLUSIONS: This study provides novel evidence of the utility of NR8383 for investigating accumulation and lysosomal sequestration of respiratory drugs in AMs.