RESUMO
AIMS AND OBJECTIVES: To explore the process by which people with hypersensitivity pneumonitis implement continuous antigen avoidance, alongside the situations that influence this process. BACKGROUND: Antigen avoidance is the primary treatment for people with hypersensitivity pneumonitis. However, the best method to support antigen avoidance has not yet been established. DESIGN: The present qualitative study used a constructivist grounded theory approach. METHODS: The participants were inpatients or outpatients with hypersensitivity pneumonitis diagnosed at a Japanese urban university hospital. In parallel with semi-structured interviews and a medical record survey from 2016 to 2021, we conducted coding, categorising, writing memos, theoretical sampling and continuous comparisons of experiences from finding physical abnormalities to implementing antigen avoidance. The COREQ checklist was followed for reporting. RESULTS: Interpreting the experiences leading to the implementation of continuous antigen avoidance by 28 participants provided a process consisting of a core category: trying to maintain one's desired life under uncertain situations, and four phases: (1) searching for a convincing cause of the illness, (2) gradually understanding the disease, (3) realising the need for behaviour change and (4) seeking a good balance between behaviour change and one's desired life. The situations that influenced the process were also revealed. CONCLUSIONS: Being convinced of the cause of one's illness and realising its severity led to the participants' realisation of the need for a behavioural change to avoid antigens. The uncertainty of the cause of illness and measures taken, a lack of clear advice from healthcare providers and one's desired life influenced participants' implementation of continuous antigen avoidance. RELEVANCE TO CLINICAL PRACTICE: This study provides important insights regarding how healthcare providers should better understand and support people with hypersensitivity pneumonitis in avoiding antigens.
Assuntos
Alveolite Alérgica Extrínseca , Humanos , Teoria Fundamentada , Pesquisa Qualitativa , Inquéritos e QuestionáriosRESUMO
Leukoencephalopathies comprise a broad spectrum of disorders, but the genetic background of adult leukoencephalopathies has rarely been assessed. In this study, we analyzed 101 Japanese patients with genetically unresolved adult leukoencephalopathy using whole-exome sequencing and repeat-primed polymerase chain reaction for detecting GGC expansion in NOTCH2NLC. NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease. We found 12 patients with GGC expansion in NOTCH2NLC as the most frequent cause of adult leukoencephalopathy followed by NOTCH3 variants in our cohort. Furthermore, we found 1 case with de novo GGC expansion, which might explain the underlying pathogenesis of sporadic cases. ANN NEUROL 2019;86:962-968.
Assuntos
Variação Genética/genética , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Receptor Notch2/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Mutations in the MATR3 gene have been identified as a cause of familial amyotrophic lateral sclerosis, but involvement of the matrin 3 (MATR3) protein in sporadic amyotrophic lateral sclerosis (SALS) pathology has not been fully assessed. We immunohistochemically analyzed MATR3 pathology in the spinal cords of SALS and control autopsy specimens. MATR3 immunostaining of the motor neuron nuclei revealed two distinct patterns: mild and strong staining. There were no differences in the ratio of mild versus strong nuclear staining between the SALS and control cases. MATR3-containing neuronal cytoplasmic inclusions (NCIs) were observed in 60% of SALS cases. Most motor neurons with MATR3-positive NCIs exhibited a mild nuclear staining pattern. Although 16.8% of NCIs positive for transactivating response region DNA-binding protein 43 (TDP-43) were estimated as double-labeled by MATR3, no MATR3-positive or TDP-43-negative NCIs were observed. Although a previous study found that MATR3-positive NCIs are present only in cases with C9orf72 hexanucleotide repeat expansion, ubiquitin-positive granular NCIs were not observed in the cerebellum, which have been reported as specific to C9orf72-related ALS. Six ALS cases were confirmed to be negative for the GGGGCC hexanucleotide. Our results reveal that MATR3 is a component of TDP-43-positive NCIs in motor neurons, even in SALS, and indicate the broader involvement of MATR3 in ALS pathology and the heterogeneity of TDP-43-positive NCIs.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Corpos de Inclusão/metabolismo , Neurônios Motores/metabolismo , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas de Ligação a RNA/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Casos e Controles , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Corpos de Inclusão/patologia , Vértebras Lombares , Masculino , Pessoa de Meia-Idade , Neurônios Motores/patologia , Medula Espinal/metabolismoRESUMO
BACKGROUND: In patients with paroxysmal nocturnal hemoglobinuria (PNH), the membrane-attack complex (MAC) formed on red blood cells (RBCs) causes hemolysis due to the patient's own activated complement system by an infection, inflammation, or surgical stress. The efficacy of transfusion therapy for patients with PNH has been documented, but no studies have focused on the perioperative use of salvaged autologous blood in patients with PNH. CASE PRESENTATION: A 71-year-old man underwent total hip replacement surgery. An autologous blood salvage device was put in place due to the large bleeding volume and the existence of an irregular antibody. The potassium concentration in the transfer bag of salvaged RBCs after the wash process was high at 6.2 mmol/L, although the washing generally removes > 90% of the potassium from the blood. This may have been caused by continued hemolysis even after the wash process. Once activated, the complement in patients with PNH forms the MAC on the RBCs, and the hemolytic reaction may not be stopped even with RBC washing. CONCLUSIONS: Packed RBCs, instead of salvaged autologous RBCs, should be used for transfusions in patients with PNH. The use of salvaged autologous RBCs in patients with PNH should be limited to critical situations, such as massive bleeding. Physicians should note that the hemolytic reaction may be present inside the transfer bag even after the wash process.
Assuntos
Artroplastia de Quadril/efeitos adversos , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/diagnóstico , Hemólise/fisiologia , Recuperação de Sangue Operatório/métodos , Idoso , Artroplastia de Quadril/tendências , Transfusão de Sangue Autóloga/métodos , Transfusão de Eritrócitos/métodos , Hemoglobinúria Paroxística/terapia , Humanos , MasculinoRESUMO
Collapsin response mediator protein 2 (CRMP2) plays a key role in axon guidance, dendritic morphogenesis and cell polarization. CRMP2 is implicated in various neurological and psychiatric disorders. However, in vivo functions of CRMP2 remain unknown. We generated CRMP2 gene-deficient (crmp2-/- ) mice and examined their behavioral phenotypes. During 24-h home cage monitoring, the activity level during the dark phase of crmp2-/- mice was significantly higher than that of wild-type (WT) mice. Moreover, the time during the open arm of an elevated plus maze was longer for crmp2-/- mice than for WT mice. The duration of social interaction was shorter for crmp2-/- mice than for WT mice. Crmp2-/- mice also showed mild impaired contextual learning. We then examined the methamphetamine-induced behavioral change of crmp2-/- mice. Crmp2-/- mice showed increased methamphetamine-induced ambulatory activity and serotonin release. Crmp2-/- mice also showed altered expression of proteins involved in GABAergic synapse, glutamatergic synapse and neurotrophin signaling pathways. In addition, SNAP25, RAB18, FABP5, ARF5 and LDHA, which are related genes to schizophrenia and methamphetamine sensitization, are also decreased in crmp2-/- mice. Our study implies that dysregulation of CRMP2 may be involved in pathophysiology of neuropsychiatric disorders.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Transtornos Mentais/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Doenças do Sistema Nervoso/metabolismo , Animais , Comportamento Animal , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Deficiências da Aprendizagem/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/metabolismo , Córtex Pré-Frontal/metabolismo , ProteomaRESUMO
In amyotrophic lateral sclerosis (ALS), neurodegeneration is characterized by distal axonopathy that begins at the distal axons, including the neuromuscular junctions, and progresses proximally in a "dying back" manner prior to the degeneration of cell bodies. However, the molecular mechanism for distal axonopathy in ALS has not been fully addressed. Semaphorin 3A (Sema3A), a repulsive axon guidance molecule that phosphorylates collapsin response mediator proteins (CRMPs), is known to be highly expressed in Schwann cells near distal axons in a mouse model of ALS. To clarify the involvement of Sema3A-CRMP signaling in the axonal pathogenesis of ALS, we investigated the expression of phosphorylated CRMP1 (pCRMP1) in the spinal cords of 35 patients with sporadic ALS and seven disease controls. In ALS patients, we found that pCRMP1 accumulated in the proximal axons and co-localized with phosphorylated neurofilaments (pNFs), which are a major protein constituent of spheroids. Interestingly, the pCRMP1:pNF ratio of the fluorescence signal in spheroid immunostaining was inversely correlated with disease duration in 18 evaluable ALS patients, indicating that the accumulation of pCRMP1 may precede that of pNFs in spheroids or promote ALS progression. In addition, overexpression of a phospho-mimicking CRMP1 mutant inhibited axonal outgrowth in Neuro2A cells. Taken together, these results indicate that pCRMP1 may be involved in the pathogenesis of axonopathy in ALS, leading to spheroid formation through the proximal progression of axonopathy.
RESUMO
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder that affects upper and lower motor neurons; however, its pathomechanism has not been fully elucidated. Using a comprehensive phosphoproteomic approach, we have identified elevated phosphorylation of Collapsin response mediator protein 1 (Crmp1) at serine 522 in the lumbar spinal cord of ALS model mice overexpressing a human superoxide dismutase mutant (SOD1G93A). We investigated the effects of Crmp1 phosphorylation and depletion in SOD1G93A mice using Crmp1S522A (Ser522âAla) knock-in (Crmp1ki/ki ) mice in which the S522 phosphorylation site was abolished and Crmp1 knock-out (Crmp1-/-) mice, respectively. Crmp1ki/ki /SOD1G93A mice showed longer latency to fall in a rotarod test while Crmp1-/-/SOD1G93A mice showed shorter latency compared with SOD1G93A mice. Survival was prolonged in Crmp1ki/ki /SOD1G93A mice but not in Crmp1-/-/SOD1G93A mice. In agreement with these phenotypic findings, residual motor neurons and innervated neuromuscular junctions (NMJs) were comparatively well-preserved in Crmp1ki/ki /SOD1G93A mice without affecting microglial and astroglial pathology. Pathway analysis of proteome alterations showed that the sirtuin signaling pathway had opposite effects in Crmp1ki/ki /SOD1G93A and Crmp1-/-/SOD1G93A mice. Our study indicates that modifying CRMP1 phosphorylation is a potential therapeutic strategy for ALS.
Assuntos
Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Fosforilação , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1/metabolismoRESUMO
BACKGROUND: Antigen avoidance (AA) is essential for people with hypersensitivity pneumonitis (HP). An intervention programme to promote continuous AA in people with HP will be the focus of future research. OBJECTIVES: We systematically analysed the AA behaviour of people with HP, interventions of health-care providers to promote AA behaviour, clinical outcomes after AA, and evaluation methods after AA. METHODS: We conducted a scoping review using six online databases and manual searches. Papers written in English or Japanese that reported cases on AA were selected. The extracted data were classified qualitatively. RESULTS: In total 205 cases included in 109 eligible papers were examined. CONCLUSIONS: This review clarified the fundamental evidence of AA in people with HP. These people required the continuous support of health-care providers to continue appropriate AA. This review highlighted four aspects that require further research to design interventions for promoting effective and continuous AA in people with HP.
Assuntos
Alveolite Alérgica Extrínseca , Pessoal de Saúde , HumanosRESUMO
Perioperative management of pregnant women with heart failure is difficult. Management of anesthesia in pregnant women is especially difficult because all of the currently available choices present challenges. We report a patient with peripartum cardiomyopathy (PPCM) who required an emergent cesarean section and discuss the possible tactics for managing anesthesia. A 40-year-old primipara with severe cardiac and respiratory failure required an emergent cesarean section at 39+1 gestational weeks. Her left ventricular ejection fraction was between 10% and 15%, and she had orthopnea. General anesthesia was planned after inserting sheaths for percutaneous cardiopulmonary support from the femoral artery and vein. However, when the patient was asked to lie down on the operation bed, she panicked and resisted because of labor pain and dyspnea. Therefore, anesthesia was induced instead of the initial plan. Finally, we successfully managed the anesthesia and delivered the newborn. There are no alternatives to general anesthesia in patients with PPCM presenting with orthopnea. Anesthesia induction in the supine position is impossible in such patients owing to dyspnea. Anesthesia should be started with light sedation in the sitting position, and ketamine or low-dose remifentanil may be an option to maintain maternal hemodynamics and prevent neonatal asphyxia.
Assuntos
Cardiomiopatias , Cesárea , Adulto , Anestesia Geral , Dispneia , Feminino , Humanos , Recém-Nascido , Período Periparto , Gravidez , Volume Sistólico , Função Ventricular EsquerdaRESUMO
AIM: Our aim was to explore changes in nutritional and activity status of patients within 6 months after transcatheter aortic valve replacement (TAVR) and factors affecting malnutrition post-TAVR in this cohort, and to gain understanding of their lifestyle considerations. METHODS: Using a mixed methods approach, we conducted a prospective, longitudinal survey, consisting of interviews and a questionnaire, of 50 participants aged ≥70 years (mean age, 83 years; 58.0% female) undergoing TAVR. Mini Nutritional Assessment (MNA) and albumin level (to measure nutritional status) and Physical Component Summary (PCS) scores from the 36-item Short Form Health Survey (to measure activity status) were collected at pre-TAVR and 1 month and 6 months post-TAVR. Laboratory data and some index scores (e.g., the Clinical Frailty Scale [CFS] and the Mini-Mental State Examination [MMSE]) assessed before TAVR were collected from medical records as related factors. RESULTS: Significant change was observed only in the MNA scores of participants who were assessed as malnourished at pre-TAVR, which improved, but did not reach normal nutritional status. Low-flow low-gradient aortic stenosis (odds ratio [OR]: 166.39, 95% confidence interval [CI]: 5.43-5094.43), higher CFS scores (OR: 2.58, 95% CI: 1.01-6.54), and lower MMSE scores (OR: 0.65, 95% CI: 0.43-0.99) were related to malnutrition post-TAVR. From interviews, three themes emerged: "balancing heart-healthy lifestyle and longstanding habits," "living with aging and disease" and "prospects for the rest of life." CONCLUSIONS: Our results could be utilized to identify patients at risk of malnutrition post-TAVR, and to provide support with consideration of their lifestyle concerns.
Assuntos
Estado Nutricional , Substituição da Valva Aórtica Transcateter , Idoso , Idoso de 80 Anos ou mais , Feminino , Implante de Prótese de Valva Cardíaca , Humanos , Estilo de Vida , Masculino , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
CRMP2, alternatively designated as DPYSL2, was the first CRMP family member to be identified as an intracellular molecule mediating the signaling of the axon guidance molecule Semaphorin 3A (Sema3A). In Sema3A signaling, cyclin-dependent kinase 5 (Cdk5) primarily phosphorylates CRMP2 at Ser522. Glycogen synthase kinase-3ß (GSK-3ß) subsequently phosphorylates the residues of Thr509 and Thr514 of CRMP2. Previous studies showed that CRMP2 is involved in pathogenesis of neurological disorders such as Alzheimer's disease. In Alzheimer's disease, hyper-phosphorylated forms of CRMP2 are accumulated in the paired helical filaments. To get insight into the possible involvement of the phosphorylation of CRMP2 in pathogenesis of neurological disorders, we previously created CRMP2 S522A knock-in (crmp2ki/ki) mice and demonstrated that the phosphorylation of CRMP2 at Ser522 is involved in normal dendrite patterning in cortical neurons. However, the behavioral impact and in vivo signaling network of the CRMP2 phosphorylation are not fully understood. In this study, we performed behavioral and proteomics analysis of crmp2ki/ki mice. The crmp2ki/ki mice appeared healthy and showed no obvious differences in physical characteristics compared to wild-type mice, but they showed impaired emotional behavior, reduced sociality, and low sensitivity to pain stimulation. Through mass-spectrometry-based proteomic analysis, we found that 59 proteins were increased and 77 proteins were decreased in the prefrontal cortex of crmp2ki/ki mice. Notably, CRMP3, CRMP4, and CRMP5, the other CRMP family proteins, were increased in crmp2ki/ki mice. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses identified 14 pathways in increased total proteins and 13 pathways in decreased total proteins which are associated with the pathogenesis of Parkinson's, Alzheimer's, and Huntington's diseases. We also detected 20 pathways in increased phosphopeptides and 16 pathways in decreased phosphopeptides including "inflammatory mediator regulation of TRP channels" in crmp2ki/ki mice. Our study suggests that the phosphorylation of CRMP2 at Ser522 is involved in the signaling pathways that may be related to neuropsychiatric and neurodegenerative diseases and pain.
Assuntos
Comportamento Animal/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Proteoma/metabolismo , Animais , Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos Transgênicos , Emaranhados Neurofibrilares/metabolismo , Neurônios/metabolismo , Fosforilação , Semaforina-3A/metabolismoRESUMO
A 69-year-old woman was admitted due to gradual progression of daytime sleepiness and forgetfulness over a period of approximately 1 month. Bradycardia and hypothermia were observed on admission, and neurological examination revealed memory disturbance, mild dysarthria, and bradykinesia. Fluid-attenuated inversion recovery (FLAIR) images of the brain magnetic resonance imaging (MRI) indicated signal hyperintensity in the region bordering the lateral and third ventricles. Serum anti-aquaporin 4 (AQP4) antibody was detected. The patient had no history or findings of optic neuritis or myelitis, and she was diagnosed as anti-AQP4 antibody-associated disorder. Diencephalon lesion and/or symptoms are rarely observed at the onset of neuromyelitis optica. Differential diagnosis of this disorder is necessary in cases manifesting diencephalon symptoms or involving lesions bordering the third ventricle without evidence of previous optic neuritis or myelitis.
Assuntos
Aquaporina 4/imunologia , Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso/complicações , Doenças Autoimunes do Sistema Nervoso/imunologia , Diencéfalo/patologia , Hipotermia/etiologia , Imageamento por Ressonância Magnética , Transtornos da Memória/etiologia , Neuromielite Óptica/etiologia , Idoso , Ventrículos Cerebrais/patologia , Disartria/etiologia , Feminino , Humanos , Hipocinesia/etiologiaRESUMO
Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias are clinically and genetically heterogeneous disorders with diverse neurological and non-neurological features. We herein describe a Japanese patient with a slowly progressive form of ataxia and spastic paraplegia. Using whole exome sequencing, we identified a novel homozygous frameshift mutation in SPG7, encoding paraplegin, in this patient. This is the first report of an SPG7 mutation in the Japanese population. For disorders previously undetected in a particular population, or unrecognized/atypical phenotypes, exome sequencing may facilitate molecular diagnosis.
Assuntos
Povo Asiático/genética , Deficiência Intelectual/genética , Metaloendopeptidases/genética , Espasticidade Muscular/genética , Mutação/genética , Atrofia Óptica/genética , Paraplegia/genética , Paraplegia Espástica Hereditária/genética , Ataxias Espinocerebelares/genética , ATPases Associadas a Diversas Atividades Celulares , Exoma/genética , Homozigoto , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Pessoa de Meia-Idade , Espasticidade Muscular/diagnóstico , Atrofia Óptica/diagnóstico , Paraplegia/diagnóstico , Linhagem , Análise de Sequência de DNA/métodos , Paraplegia Espástica Hereditária/diagnóstico , Ataxias Espinocerebelares/diagnósticoAssuntos
Militares , Trabalho de Resgate , Transtornos de Estresse Traumático Agudo/prevenção & controle , Estresse Psicológico/terapia , Adaptação Psicológica/fisiologia , Adulto , Humanos , Japão , Masculino , Transtornos de Estresse Traumático Agudo/fisiopatologia , Transtornos de Estresse Traumático Agudo/psicologia , Estresse Psicológico/psicologiaRESUMO
Bisphenol A (BPA) is a weakly estrogenic monomer used to produce polymers for food contact and other applications, so there is potential for oral exposure of humans to trace amounts via ingestion. To date, no physiologically based pharmacokinetic (PBPK) model has been located for BPA in pregnant mice with or without fetuses. An estimate by a mathematical model is essential since information on humans is difficult to obtain experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of BPA to pregnant mice. The risk assessment of bisphenol A (BPA) on the development of human offspring is an important issue. There have been limited data on the exposure level of human fetuses to BPA (e.g. BPA concentration in cord blood) and no information is available on the pharmacokinetics of BPA in humans with or without fetuses. In the present study, we developed a physiologically based pharmacokinetic (PBPK) model describing the pharmacokinetics of BPA in a pregnant mouse with the prospect of future extrapolation to humans. The PBPK model was constructed based on the pharmacokinetic data of an experiment we executed on pregnant mice following single oral administration of BPA. The model could describe the rapid transfer of BPA through the placenta to the fetus and the slow disappearance from fetuses. The simulated time courses after three-time repeated oral administrations of BPA by the constructed model fitted well with the experimental data, and the simulation for the 10 times lower dose was also consistent with the experiment. This suggested that the PBPK model for BPA in pregnant mice was successfully verified and is highly promising for extrapolation to humans who are expected to be exposed more chronically to lower doses.
Assuntos
Estrogênios não Esteroides/farmacocinética , Troca Materno-Fetal , Modelos Biológicos , Fenóis/farmacocinética , Medição de Risco/métodos , Administração Oral , Animais , Compostos Benzidrílicos , Simulação por Computador , Esquema de Medicação , Estrogênios não Esteroides/administração & dosagem , Feminino , Sangue Fetal , Feto/metabolismo , Humanos , Camundongos , Fenóis/administração & dosagem , Placenta/metabolismo , Gravidez , Reprodutibilidade dos Testes , Especificidade da Espécie , Distribuição TecidualRESUMO
Endosulfan, an organochlorine (OC) insecticide that belongs to the cyclodiene group, is one of the most commonly used pesticides to control pests in vegetables, cotton, and fruits. Porcine brain microvascular endothelial cells were used to develop a model to study the effects of endosulfan on the permeability of tight junctions in the blood-brain barrier (BBB). BBB permeability, measured as transendothelial electrical resistance, decreased in a dose- and time-dependent manner when treated with alpha-endosulfan, beta-endosulfan, or endosulfan sulfate. Cytotoxicity testing revealed that the three endosulfans did not cause cell death at concentrations of 10 microM and below. The ratio of the average permeability of the filter-grown endothelial cell monolayer to 14C-endosulfan (Pe) going from the outer to the inner compartments with that going from the inner to the outer compartments was approximately 1:1.2-2.1 after exposure to concentrations of 0.01-10 microM. alpha-Endosulfan, beta-endosulfan, and endosulfan sulfate had cytotoxic effects on rat glial (C6) and neuronal (PC12) cell cultures as well as on human glial (CCF-STTG1) and neuronal (NT2) cell cultures. The effects of alpha-endosulfan were highly selective, with a wide range of LC50 values found in the different cultures, ranging from 11.2 microM for CCF-STTG1 cells to 48.0 microM for PC12 cells. In contrast, selective neurotoxicity was not so manifest in glial and neuronal cell cultures after exposure to endosulfan sulfate, as LC50 values were in the range of 10.4-21.6 microM. CCF-STTG1 cells were more sensitive to alpha-endosulfan and endosulfan sulfate, whereas NT2 cells were more sensitive to beta-endosulfan.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Endossulfano/toxicidade , Inseticidas/toxicidade , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Barreira Hematoencefálica/metabolismo , Radioisótopos de Carbono , Células Cultivadas , Humanos , Modelos Biológicos , Neuroglia/citologia , Neuroglia/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Permeabilidade , Ratos , Fatores de TempoRESUMO
Endosulfan, an organochlorine (OC) insecticide belonging to the cyclodiene group, is one of the most commonly used pesticides to control pests in vegetables, cotton, and fruits. To date, no physiologically based pharmacokinetic (PBPK) model has been located for endosulfan in animal species and humans. The estimation by a mathematical model is essential since information on humans can scarcely be obtained experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of (14)C-Endosulfan to male Sprague-Dawley rats. The model was parameterized by using reference physiological parameter values and partition coefficients that were determined in the experiment and optimized by manual adjustment until the best visual fit of the simulations with the experimental data were observed. The model was verified by simulating the disposition of (14)C-Endosulfan in vivo after single and multiple oral dosages and comparing simulated results with experimental results. The model was further verified by using experimental data retrieved from the literature. The present model could reasonably predict target tissue dosimetries in rats. Simulation with three-time repeated administration of (14)C-Endosulfan and experimental data retrieved from the literature by the constructed model fitted fairly well with the experimental results; thus suggesting that the newly developed PBPK model was developed. Sensitivity analyses were used to determine those input parameters with the greatest influence on endosulfan tissue concentrations.
Assuntos
Endossulfano/farmacocinética , Modelos Biológicos , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Calibragem , Endossulfano/administração & dosagem , Endossulfano/sangue , Endossulfano/farmacologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Sensibilidade e EspecificidadeRESUMO
Endosulfan (ES), an organochlorine (OC) insecticide that belongs to the cyclodiene group, is one of the most commonly used pesticides to control pests in vegetables, cotton, and fruits. The toxicokinetics of 14C-endosulfan following oral administration of a single dose of 5 mg/kg body weight was investigated in male Sprague-Dawley rats. Three rats were sacrificed 30 min, 1 h, 2 h, 4 h, and 8 h after dosing. 14C-endosulfan radioactivity was detected in all tissues at each time point. In a separate experiment urine and feces were collected for 96 h. The total radioactivity recovered in the excreta for 4 days was 106.8% +/- 26.2%, with fecal elimination the major route of elimination route (94.4% +/- 21.4%). The cumulative excretion in the urine for 4 days was 12.4% +/- 4.8%. Radioactivity 8 h after administration was highest in gastrointestinal (GI) tract tissue (20.28 +/- 16.35 mg ES eq./L) and lowest in muscle (0.18 +/- 0.06 mg ES eq./L). The toxicokinetic parameters obtained from 14C-endosulfan-derived radioactivity in blood were distribution half-life (T1/2 x) = 31 min and terminal elimination half-life (T1/2 y) = 193 h. Blood concentration reached its maximum (Cmax) of 0.36 +/- 0.08 mg ES eq./L 2 h after the oral dose. Endosulfan was rapidly absorbed into the GI tract in rats, with an absorption rate constant (ka) of 3.07 h(-1).