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The source and dynamics of calcium is the key factor that regulates dendritic integration. Apart from the voltage-gated and ligand-gated calcium influx, an important source of calcium is from inner store of endoplasmic reticulum with a regenerative process of calcium-induced calcium release (CICR). To trigger this process, inositol 1,4,5-trisphosphate (IP3) and calcium are needed to satisfy certain requirements. The aim of our paper is to investigate how the CICR depends on the dynamics of membrane potential. We utilize one dimensional dendritic model to calculate membrane potential by Nernst-Planck Equation (NPE) and cable model and Pure Diffusion (PD) model, computational simulations are carried out to inject the calcium influx by synaptic stimulation and to predict subsequent CICR and calcium wave propagation. Our results demonstrate that CICR initiation and calcium wave propagation have much difference between electro-diffusion process of NPE and cable model. We find that cable model has lower threshold of IP3 stimulation to trigger CICR but is more difficult for calcium propagation than NPE, PD model requires even higher threshold of IP3 to initiate CICR process and calcium duration is shorter than NPE; the regenerative calcium wave propagates with faster speed in NPE than that in cable model and in PD model. Our work addresses the important role of electro-diffusion dynamics of charged ions in regulating CICR process in dendritic structure; and provides theoretical predictions for neurological process which requires sustaining calcium for downstream signaling processes.
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INTRODUCTION: Traditionally echocardiography was used by pediatric cardiologists to diagnose congenital heart defects in neonates. Formalized neonatal hemodynamic fellowships have been established where neonatologists acquire advanced echocardiographic skills to gain anatomical, physiological, and hemodynamic information in real time and utilize this information in making a timely and accurate physiology-based clinical decision. AREA COVERED: Differences between a comprehensive formal structural echocardiography, neonatologist performed targeted echocardiography and limited assessment on point-of-care-ultrasonography for specific indications have been covered. This article is focused at providing a comprehensive review of the status of echocardiography in the neonatal units, recent advancements and its future prospects in the neonatal intensive care units. EXPERT OPINION: Comprehensive guidelines providing the scope of practice, a framework for training, and robust clinical governance process for the neonatologist performed targeted echocardiography have been established. In the last decade, echocardiography has emerged as essential vital bedside diagnostic tool in providing high-quality care to the sick infants in the neonatal units, and it has proved to improve the outcomes in neonates. It is now being considered as a modern hemodynamic monitoring tool. Advances in technology, machine learning, and application of artificial intelligence in applications of echocardiography seem promising adjunct tools for rapid assessment in emergency situations.
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Details of the structural elucidation of the clinically useful photodynamic therapy sensitizer NPe6 (15) are presented. NPe6, also designated as Laserphyrin, Talaporfin, and LS-11, is a second-generation photosensitizer derived from chlorophyll-a, currently used in Japan for the treatment of human lung, esophageal, and brain cancers. After the initial misidentification of the structure of this chlorin-e6 aspartic acid conjugate as (13), NMR and other synthetic procedures described herein arrived at the correct structure (15), confirmed using single crystal X-ray crystallography. Interesting new features of chlorin-e6 chemistry (including the intramolecular formation of an anhydride (24)) are reported, allowing chemists to regioselectively conjugate amino acids to each available carboxylic acid on positions 131 (formic), 152 (acetic), and 173 (propionic) of chlorin e6 (14). Cellular investigations of several amino acid conjugates of chlorin-e6 revealed that the 131-aspartylchlorin-e6 derivative is more phototoxic than its 152- and 173-regioisomers, in part due to its nearly linear molecular conformation.
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Clorofilidas , Fotoquimioterapia , Porfirinas , Humanos , Fármacos Fotosensibilizantes/química , Fotoquimioterapia/métodos , Porfirinas/química , Aminoácidos , Ácido Aspártico/químicaRESUMEN
Direct-to-consumer DNA tests provide information on ancestry and family relations. Their increased use in recent years has led many to discover that their presumed father is not their biological father, a non-paternity event (NPE). We aimed to explore and quantify the psychiatric effects of discovering one's father's identity was misattributed. We distributed questionnaires in a private online community of individuals who learned they were NPEs. Questionnaires included clinical scales assessing depressive, anxiety, and panic symptomatology as well as background and personal details regarding participants' NPE discovery and demography. A total of 731 people participated. Results demonstrated increased levels of depression, anxiety, and panic symptoms relative to controls. Multiple factors influenced such effects, including demographics, background information, family members' reactions, and personal reactions. We identified a worsening relationship or attitude toward the mother as a risk factor for worse mental health. The ability to openly discuss the discovery and acceptance of it were identified as protective factors. This is the first paper to explore the psychiatric sequelae of discovering misattributed paternity in a large cohort. This unique psychosocial stressor is likely to become more common as direct-to-consumer DNA tests gain popularity, requiring the attention of mental health professionals.
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Padre , Paternidad , Masculino , Femenino , Humanos , Relaciones Familiares , Actitud , ADNRESUMEN
BACKGROUND: Photodynamic therapy (PDT) is a cancer-targeted treatment that uses a photosensitizer (PS) and laser irradiation. The effectiveness of current PDT using red light for advanced cancers is limited, because red light can only reach depths within a few millimeters. To enhance the antitumor effect for lung cancers, we developed a new phototherapy, intelligent targeted antibody phototherapy (iTAP). This treatment uses a combination of immunotoxin and a PS, mono-L-aspartyl chlorin e6 (NPe6). METHODS: We examined whether cetuximab encapsulated in endosomes was released into the cytosol by PS in PDT under light irradiation. A431 cells were treated with fluorescein isothiocyanate-labeled cetuximab, NPe6, and light irradiation and were observed with fluorescence microscopy. We analyzed the cytotoxicity of saporin-conjugated cetuximab (IT-cetuximab) in A431, A549, and MCF7 cells and the antitumor effect in model A549-bearing mice in vivo using the iTAP method. RESULTS: Fluorescent microscopy analysis showed that the photodynamic effect of NPe6 (20 µM) and light irradiation (37.6 J/cm2 ) caused the release of cetuximab from the endosome into the cytosol. In vitro analysis demonstrated that the iTAP method enhanced the cytotoxicity of IT-cetuximab by the photodynamic effect. In in vivo experiments, compared with IT-cetuximab alone or PDT alone, the iTAP method using a low dose of IT-cetuximab showed the greatest enhancement of the antitumor effect. CONCLUSIONS: Our study is the first report of the iTAP method using NPe6 for lung cancer cells. The iTAP method may become a new, minimally invasive treatment superior to current PDT methods.
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Inmunotoxinas , Neoplasias Pulmonares , Fotoquimioterapia , Humanos , Animales , Ratones , Fotoquimioterapia/métodos , Inmunotoxinas/farmacología , Inmunotoxinas/uso terapéutico , Cetuximab/farmacología , Cetuximab/uso terapéutico , Fototerapia , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
We revealed the difference in the mechanism of photodynamic therapy (PDT) between two photosensitizers: porphylipoprotein (PLP), which has recently attracted attention for its potential to be highly effective in treating cancer, and talaporphyrin sodium (NPe6). (1) NPe6 accumulates in lysosomes, whereas PLP is incorporated into phagosomes formed by PLP injection. (2) PDT causes NPe6 to generate reactive oxygen species, thereby producing actin filaments and stress fibers. In the case of PLP, however, reactive oxygen species generated by PDT remain in the phagosomes until the phagosomal membrane is destroyed, which delays the initiation of RhoA activation and RhoA*/ROCK generation. (4) After the disruption of the phagosomal membrane, however, the outflow of various reactive oxygen species accelerates the production of actin filaments and stress fibers, and blebbing occurs earlier than in the case of NPe6. (5) PLP increases the elastic modulus of cells without RhoA activity in the early stage. This is because phagosomes are involved in polymerizing actin filaments and pseudopodia formation. Considering the high selectivity and uptake of PLP into cancer cells, a larger effect with PDT can be expected by skillfully combining the newly discovered characteristics, such as the appearance of a strong effect at an early stage.
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Fotoquimioterapia , Porfirinas , Especies Reactivas de Oxígeno , Sodio , Porfirinas/farmacología , Fármacos Fotosensibilizantes/uso terapéuticoRESUMEN
Acute dyspnea is one of the most common presentations in acute/emergency settings, and acute pulmonary edema remains a leading cause in adults resulting from either cardiogenic or non-cardiogenic etiologies. Neurogenic pulmonary edema (NPE) is one of the less common forms of non-cardiogenic pulmonary edema seen in emergency departments, neurology units, or intensive care units. It usually develops rapidly following significant neurological insult seen in patients with intracranial hemorrhage, traumatic brain injuries, and epileptic seizures. It is less commonly seen after a multitude of other sudden catastrophic neurologic insults. Here, we report a case study of a 32-year-old female with a history of epilepsy since childhood who was admitted to our respiratory admission unit on two separate occasions with acute NPE and type I respiratory failure after a witnessed tonic-clonic seizure episode. Although the clinical features of NPE and the results of investigations can mimic more common cardiorespiratory conditions, an accurate and timely diagnosis is vital for the appropriate emergency management and to improve the patient's outcome.
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High dimensionality data have become common in neuroimaging fields, especially group-level functional magnetic resonance imaging (fMRI) datasets. fMRI connectivity analysis is a widely used, powerful technique for studying functional brain networks to probe underlying mechanisms of brain function and neuropsychological disorders. However, data-driven technique like independent components analysis (ICA), can yield unstable and inconsistent results, confounding the true effects of interest and hindering the understanding of brain functionality and connectivity. A key contributing factor to this instability is the information loss that occurs during fMRI data reduction. Data reduction of high dimensionality fMRI data in the temporal domain to identify the important information within group datasets is necessary for such analyses and is crucial to ensure the accuracy and stability of the outputs. In this study, we describe an fMRI data reduction strategy based on an adapted neighborhood preserving embedding (NPE) algorithm. Both simulated and real data results indicate that, compared with the widely used data reduction method, principal component analysis, the NPE-based data reduction method (a) shows superior performance on efficient data reduction, while enhancing group-level information, (b) develops a unique stratagem for selecting components based on an adjacency graph of eigenvectors, (c) generates more reliable and reproducible brain networks under different model orders when the outputs of NPE are used for ICA, (d) is more sensitive to revealing task-evoked activation for task fMRI, and (e) is extremely attractive and powerful for the increasingly popular fast fMRI and very large datasets.
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Algoritmos , Imagen por Resonancia Magnética , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Mapeo Encefálico/métodos , Humanos , Imagen por Resonancia Magnética/métodos , Análisis de Componente PrincipalRESUMEN
Pulmonary mucoepidermoid carcinoma (PMEC) are rare, accounting for 0.1-0.2% of all malignant lung tumors. Furthermore, endobronchial lesions are rare and are more commonly found in the segmental or lobar bronchi. We present, to the best of our knowledge, the first case of successful treatment with photodynamic therapy (PDT) for PMEC. A 77-year-old male presented with cough and hemosputum for 4 months. Chest computed tomography showed a mass in the right intermediate bronchus. Endobronchial biopsy revealed a diagnosis of PMEC. An optimal surgical technique to preserve respiratory function was desirable as most of the tumor emerged from the bronchial glands in the central airways and was of low-grade type. Hence, PDT was performed. Repeat bronchoscopies were performed 5 years after the PDT and showed no evidence of tumor recurrence. PDT is more likely to be effective for low-grade PMECs that are visible on bronchoscopy.
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Cardiac point of care ultrasound (POCUS) is increasingly being utilized in neonatal intensive care units to provide information in real time to aid clinical decision making. While training programs and scope of practice have been well defined for other specialties, such as adult critical care and emergency medicine, there is a lack of structure for neonatal cardiac POCUS. A more comprehensive and advanced hemodynamic evaluation by a neonatologist has previously published its own clinical guidelines and specific rigorous training programs have been established to achieve competency in neonatal hemodynamics. However, it is becoming increasingly evident that access and training for basic cardiac assessment by ultrasound enhances bedside clinical care for specific indications. Recently, expert consensus POCUS guidelines for use in neonatal and pediatric intensive care endorsed by the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) have been published to guide the clinicians in using POCUS for specific indications, though the line between cardiac POCUS and advanced hemodynamic evaluation remains somewhat fluid.Conclusion: This article is focused on neonatal cardiac POCUS and its evolution, value, and limitations in the modern neonatal clinical practice. Cardiac POCUS can provide physiological and hemodynamic information in making clinical decisions while dealing with neonatal emergencies. However, it should be applied only for the specific indications and should be performed by a clinician trained in cardiac POCUS. There is an urgent need of developing cardiac POCUS curriculum and certification to support a widespread and safe use in neonates. What is Known: ⢠International training guidelines and curriculum have been published for neonatologist-performed echocardiography (NPE) or targeted neonatal echocardiography (TNE). ⢠International evidence-based guidelines for use of point of care ultrasound (POCUS) in neonates and children have been recently published. What is New: ⢠Cardiac POCUS is increasingly being incorporated in neonatal practice for emergency situations. However, one must be aware of its specific indications and limitations, especially for the neonatal clinical practice. ⢠Cardiac POCUS and NPE/TNE are continuum of cardiac imaging with different indications and training requirements.
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Neonatólogos , Sistemas de Atención de Punto , Niño , Curriculum , Ecocardiografía , Humanos , Recién Nacido , UltrasonografíaRESUMEN
Background: Patent ductus arteriosus (PDA) treatment remains controversial. Modeling on the predictive capacity of early spontaneous PDA closure would help in decision-making. Aim: To design a predictive model of early spontaneous PDA closure. Methods: As part of a trial to assess efficacy and safety of two ibuprofen treatment schemes for PDA, infants below 29 weeks' gestation were scanned between 18 and 72 h of birth, and serially if indicated. PDA treatment was decided based on echocardiography signs of lung overflow or systemic hypoperfusion and clinical criteria. A PDA score that included the echocardiographic parameters significantly associated with treatment prescription was retrospectively applied. Perinatal variables and screening score were included in a backwards elimination model to predict early spontaneous closure. Results: Among 87 eligible infants (27 weeks' gestation; age at screening 45 h), 21 received ibuprofen at 69 h of life [screening score = 7 (IQR = 5-8.5); score at treatment = 9 (IQR = 8-9)], while 42 infants had conservative management, [screening score = 1 (IQR = 0-4)]. Twenty four infants were excluded (ibuprofen contraindication, declined consent or incomplete echocardiography). Screening score showed an AUC = 0.93 to predict early spontaneous PDA closure, [cut-off value = 4.5 (sensitivity = 0.90, specificity = 0.86)]. The predictive model for early spontaneous PDA closure followed the equation: Log (p/1-p) = -28.41 + 1.23* gestational age -0.87* PDA screening score. Conclusions: A predictive model of early spontaneous PDA closure that includes gestational age and the screening PDA score is proposed to help clinicians in the decision- making for PDA treatment. In addition, this model could be used in future intervention trials aimed to prevent PDA related morbidities to improve the eligibility criteria.
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This study constructed a new non-linear model of myocardial electrical conduction block during photosensitization reaction to identify the vulnerable cell population and generate an index for recurrent risk following catheter ablation for tachyarrhythmia. A three-compartment model of conductive, vulnerable, and blocked cells was proposed. To determine the non-linearity of the rate parameter for the change from vulnerable cells to conductive cells, we compared a previously reported non-linear model and our newly proposed model with non-linear rate parameters in the modeling of myocardial cell electrical conduction block during photosensitization reaction. The rate parameters were optimized via a bi-nested structure using measured synchronicity data during the photosensitization reaction of myocardial cell wires. The newly proposed model had a better fit to the measured data than the conventional model. The sum of the error until the time where the measured value was higher than 0.6, was 0.22 in the conventional model and 0.07 in our new model. The non-linear rate parameter from the vulnerable cell to the conductive cell compartment may be the preferred structure of the electrical conduction block model induced by photosensitization reaction. This simulation model provides an index to evaluate recurrent risk after tachyarrhythmia catheter ablation by photosensitization reaction. A three-compartment non-linear model of myocardial cell conduction block during photosensitization.
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Ablación por Catéter , Fotoquimioterapia , Porfirinas , Miocitos Cardíacos , Dinámicas no Lineales , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéuticoRESUMEN
BACKGROUND/AIM: Despite improvements in cancer therapy, life expectancy after tumor recurrence remains low. Relapsed cancer is characterized by drug resistance, often mediated through overexpression of multidrug resistance (MDR) genes. Camellia sinensis non fermentatum extract is known for its anticancer properties in several cancer cell lines and might improve cancer therapy outcome after tumor recurrence. MATERIALS AND METHODS: Embryonal rhabdomyosarcoma cell lines, alveolar rhabdomyosarcoma cell lines and primary rhabdomyosarcoma MAST139 cells were used to test NPE® effects on cell viability in combination with chemotherapeutic agents. Cell viability was measured by the WST-1 assay and CV staining. Gene expression levels of chemotherapy-induced efflux pumps and their activity was assessed upon NPE® treatment by measuring doxorubicin retention through evaluation of the autofluorescence signal. RESULTS: Administration of increasing doxorubicin concentrations triggered immediate adaptation to the drug, which was surprisingly overcome by the addition of NPE®. Investigating the mechanism of immediate adaptation, MDR1 gene overexpression was observed upon doxorubicin treatment. Although NPE® did not alter pump gene expression, it was able to reduce pump activity, thus allowing the chemotherapeutic agent to stay inside the cells to exert its full anticancer activity. CONCLUSION: NPE® might improve chemotherapeutic treatment by re-sensitizing relapsed tumors to anticancer drugs. Fighting MDR represents the key to overcome tumor relapse and improve the overall survival of cancer patients.
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Antineoplásicos/farmacología , Camellia sinensis/química , Recurrencia Local de Neoplasia/tratamiento farmacológico , Rabdomiosarcoma Alveolar/tratamiento farmacológico , Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Rabdomiosarcoma Alveolar/patologíaRESUMEN
Persistent alterations of proopiomelanocortin (Pomc) and mu-opioid receptor (Oprm1) activity and stress responses after alcohol are critically involved in vulnerability to alcohol dependency. Gene transcriptional regulation altered by alcohol may play important roles. Mice with genome-wide deletion of neuronal Pomc enhancer1 (nPE1-/- ), had hypothalamic-specific partial reductions of beta-endorphin and displayed lower alcohol consumption, compared to wildtype littermates (nPE1+/+ ). We used RNA-Seq to measure steady-state nuclear mRNA transcripts of opioid and stress genes in hypothalamus of nPE1+/+ and nPE1-/- mice after 1-day acute withdrawal from chronic excessive alcohol drinking or after water. nPE1-/- had lower basal Pomc and Pdyn (prodynorphin) levels compared to nPE1+/+ , coupled with increased basal Oprm1 and Oprk1 (kappa-opioid receptor) levels, and low alcohol drinking increased Pomc and Pdyn to the basal levels of nPE1+/+ in the water group, without significant effects on Oprm1 and Oprk1. In nPE1+/+ , excessive alcohol intake increased Pomc and Oprm1, with no effect on Pdyn or Oprk1. For stress genes, nPE1-/- had lowered basal Oxt (oxytocin) and Avp (arginine vasopressin) that were restored by low alcohol intake to basal levels of nPE1+/+ . In nPE1+/+ , excessive alcohol intake decreased Oxt and Avpi1 (AVP-induced protein1). Functionally examining the effect of pharmacological blockade of mu-opioid receptor, we found that naltrexone reduced excessive alcohol intake in nPE1+/+ , but not nPE1-/- . Our results provide evidence relevant to the transcriptional profiling of the critical genes in mouse hypothalamus: enhanced opioid and reduced stress gene transcripts after acute withdrawal from excessive alcohol may contribute to altered reward and stress responses.
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Consumo Excesivo de Bebidas Alcohólicas/genética , Elementos de Facilitación Genéticos/genética , Hipotálamo/metabolismo , Proopiomelanocortina/genética , Animales , Arginina Vasopresina/metabolismo , Consumo Excesivo de Bebidas Alcohólicas/metabolismo , Encefalinas/genética , Encefalinas/metabolismo , Etanol/farmacología , Hipotálamo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Oxitocina/metabolismo , Proopiomelanocortina/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , TranscriptomaRESUMEN
A fixed dose combination of bupropion (BPP) and naltrexone (NTX), Contrave®, is an FDA approved pharmacotherapy for the treatment of obesity. A recent study found that combining BPP with low-dose NTX reduced alcohol drinking in alcohol-preferring male rats. To explore potential pharmacological effects of the BPPâ¯+â¯NTX combination on alcohol drinking, both male and female C57Bl/6J mice were tested on one-week drinking-in-the dark (DID) and three-week intermittent access (IA) models. Neuronal proopiomelanocortin (POMC) enhancer knockout (nPE-/-) mice with hypothalamic-specific deficiency of POMC, and its bioactive peptides melanocyte stimulating hormone and beta-endorphin, were used as a genetic control for the effects of the BPPâ¯+â¯NTX. A single administration of BPPâ¯+â¯NTX (10â¯mg/kgâ¯+â¯1â¯mg/kg) decreased alcohol intake after DID in C57Bl/6J males, but not females. Also in C57Bl/6J males, BPPâ¯+â¯NTX reduced intake of the caloric reinforcer sucrose, but not the non-caloric reinforcer saccharin. In contrast, BPPâ¯+â¯NTX had no effect on alcohol DID in nPE-/- males. Pretreatment with the selective melanocortin 4 receptor (MC4R) antagonist HS014 reversed the anti-dipsogenic effect of BPPâ¯+â¯NTX on alcohol DID in C57Bl/6J males. In the 3-week chronic IA model, single or repeated administrations for four days of BPPâ¯+â¯NTX reduced alcohol intake and preference in C57Bl/6J males only. The behavioral measures observed in C57Bl/6J mice provide clear evidence that BPPâ¯+â¯NTX profoundly reduced alcohol drinking in males, but the doses tested were not effective in females. Furthermore, our results suggest a hypothalamic POMC/MC4R-dependent mechanism for the observed BPPâ¯+â¯NTX effects on alcohol drinking in male mice.
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Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Alcoholismo/tratamiento farmacológico , Bupropión/farmacología , Bupropión/uso terapéutico , Evaluación Preclínica de Medicamentos/métodos , Naltrexona/farmacología , Naltrexona/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Bupropión/administración & dosificación , Combinación de Medicamentos , Sinergismo Farmacológico , Etanol/administración & dosificación , Femenino , Técnicas de Inactivación de Genes , Hipotálamo/metabolismo , Inyecciones Intraperitoneales , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Naltrexona/administración & dosificación , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/uso terapéutico , Fotoperiodo , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Receptor de Melanocortina Tipo 4/metabolismo , Sacarina/farmacología , Factores Sexuales , Sacarosa/farmacologíaRESUMEN
BACKGROUND: Nalfurafine is the first clinically approved kappa-opioid receptor (KOP-r) agonist as an antipruritus drug with few side effects in humans (e.g., sedation, depression, and dysphoria). No study, however, has been done using nalfurafine on alcohol drinking in rodents or humans. METHODS: We investigated whether nalfurafine alone or in combination with mu-opioid receptor (MOP-r) antagonist naltrexone changed excessive alcohol drinking in male and female C57BL/6J (B6) mice subjected to a chronic intermittent-access drinking paradigm (2-bottle choice, 24-hour access every other day) for 3 weeks. Neuronal proopiomelanocortin enhancer (nPE) knockout mice with brain-specific deficiency of beta-endorphin (endogenous ligand of MOP-r) were used as a genetic control for the naltrexone effects. RESULTS: Single administration of nalfurafine decreased alcohol intake and preference in both male and female B6 mice in a dose-dependent manner. Pretreatment with nor-BNI (a selective KOP-r antagonist) blocked the nalfurafine effect on alcohol drinking, indicating a KOP-r-mediated mechanism. Pharmacological effects of a 5-dosing nalfurafine regimen were further evaluated: The repeated nalfurafine administrations decreased alcohol consumption without showing any blunted effects, suggesting nalfurafine did not develop a tolerance after the multidosing regimen tested. Nalfurafine did not produce any sedation (spontaneous locomotor activity), anhedonia-like (sucrose preference test), anxiety-like (elevated plus maze test), or dysphoria-like (conditioned place aversion test) behaviors, suggesting that nalfurafine had few side effects. Investigating synergistic effects between low-dose naltrexone and nalfurafine, we found that single combinations of nalfurafine and naltrexone, at doses lower than individual effective dose, profoundly decreased excessive alcohol intake in both sexes. The effect of nalfurafine on decreasing alcohol consumption was confirmed in nPE-/- mice, suggesting independent mechanisms by which nalfurafine and naltrexone reduced alcohol drinking. CONCLUSION: The clinically utilized KOP-r agonist nalfurafine in combination with low-dose naltrexone has potential in alcoholism treatment.
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Disuasivos de Alcohol/administración & dosificación , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Trastornos Relacionados con Alcohol/tratamiento farmacológico , Morfinanos/uso terapéutico , Naltrexona/administración & dosificación , Compuestos de Espiro/uso terapéutico , Animales , Evaluación Preclínica de Medicamentos , Tolerancia a Medicamentos , Femenino , Masculino , Ratones Endogámicos C57BL , Morfinanos/farmacología , Naltrexona/análogos & derivados , Receptores Opioides kappa/agonistas , Sacarina/administración & dosificación , Compuestos de Espiro/farmacología , Sacarosa/administración & dosificaciónRESUMEN
Residual chemicals on personal care and healthcare products, such as sanitary articles, sterile gauze bandages, nappies, plasters, were studied by direct analysis in real time mass spectrometry (DART-MS). We have identified around 40 compounds in seventeen different commercially available items. The tentative identification was further supported for about half of the chemicals by tandem mass spectrometric experiments (DART MS/MS). The most notable hazardous substances were tributyl phosphate, tris(2,4-di-tert-butylphenyl) phosphite, phthalic acid esters, erucamide, and nonylphenol ethoxylates (NPEs). In addition, we developed an efficient DART-MS analysis to determine the concentration of NPE in a swab sample. The quantitative result obtained by DART-MS was confirmed by liquid chromatography with mass spectrometric detection (LC-MS).
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Materiales Manufacturados/análisis , Compuestos Orgánicos/análisis , Espectrometría de Masas en Tándem/métodos , Límite de DetecciónRESUMEN
OBJECTIVE: To investigate the effect of photodynamic therapy (PDT) with the talaporfin sodium (mono-L-asparthyl chlorine e6: NPe-6) on human malignant meningioma cell line HKBMM cells in vitro. MATERIAL AND METHODS: After incubation with NPe6 for 4 h, cells underwent PDT (diode laser irradiation: 3.4 mW/cm2 and 1 J/cm2. Cell viability was determined in 2 malignant meningioma cell lines (human origin; HKBMM cells and rat origin; KMY-J cells) and human malignant glioma U251 cells with Cell Counting Kit-8 assay. The HKBMM cells were examined for caspase-3 activity, annexin V or propidium iodide (PI) staining, and lactate dehydrogenase leakage. Morphological change was also investigated with phase-contrast microscopy. RESULTS: In human malignant meningioma HKBMM cells, viability showed a dose- and time-dependent decrease. After 24 h of laser irradiation, NPe6 at 20 µg/ml or more induced a significant decrease in cell viability in both HKBMM cells and KMY-J cells, although they more resistance than the malignant glioma cell line U251 cells. Two kinds of morphological change were also observed in the HKBMM cells, shrinkage of the cell body, indicating apoptosis, and swelling of the cell body, indicating necrosis. In addition, both caspase-3 activity and DNA fragmentation, biochemical markers indicative of apoptosis, showed a dose-dependent increase. The percentage of necrotic cells showing positive staining for annexin V or PI was greater than that of apoptotic cells at a high concentration of NPe6. Lactate dehydrogenase leakage, a biochemical marker of necrosis, also showed a marked increase at a high concentration of NPe6. CONCLUSION: Photodynamic therapy with NPe6 induced dose- and time-dependent apoptosis in human malignant meningioma HKBMM cells. At a high concentration of NPe6, however, it induced necrosis.