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1.
Neural Netw ; 166: 446-458, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37566955

RESUMO

Neural architecture search (NAS) is a framework for automating the design process of a neural network structure. While the recent one-shot approaches have reduced the search cost, there still exists an inherent trade-off between cost and performance. It is important to appropriately stop the search and further reduce the high cost of NAS. Meanwhile, the differentiable architecture search (DARTS), a typical one-shot approach, is known to suffer from overfitting. Heuristic early-stopping strategies have been proposed to overcome such performance degradation. In this paper, we propose a more versatile and principled early-stopping criterion on the basis of the evaluation of a gap between expectation values of generalisation errors of the previous and current search steps with respect to the architecture parameters. The stopping threshold is automatically determined at each search epoch without cost. In numerical experiments, we demonstrate the effectiveness of the proposed method. We stop the one-shot NAS algorithms and evaluate the acquired architectures on the benchmark datasets: NAS-Bench-201 and NATS-Bench. Our algorithm is shown to reduce the cost of the search process while maintaining a high performance.


Assuntos
Algoritmos , Redes Neurais de Computação , Aprendizado Profundo , Aprendizado de Máquina
2.
Drug Metab Dispos ; 51(6): 733-742, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36927840

RESUMO

Nintedanib, which is used to treat idiopathic pulmonary fibrosis and non-small cell lung cancer, is metabolized to a pharmacologically inactive carboxylate derivative, BIBF1202, via hydrolysis and subsequently by glucuronidation to BIBF1202 acyl-glucuronide (BIBF1202-G). Since BIBF1202-G contains an ester bond, it can be hydrolytically cleaved to BIBF1202. In this study, we sought to characterize these metabolic reactions in the human liver and intestine. Nintedanib hydrolysis was detected in human liver microsomes (HLMs) (Clearance [CL int]: 102.8 ± 18.9 µL/min per mg protein) but not in small intestinal preparations. CES1 was suggested to be responsible for nintedanib hydrolysis according to experiments using recombinant hydrolases and hydrolase inhibitors as well as proteomic correlation analysis using 25 individual HLM. BIBF1202 glucuronidation in HLM (3.6 ± 0.3 µL/min per mg protein) was higher than that in human intestinal microsomes (1.5 ± 0.06 µL/min per mg protein). UGT1A1 and gastrointestinal UGT1A7, UGT1A8, and UGT1A10 were able to mediate BIBF1202 glucuronidation. The impact of UGT1A1 on glucuronidation was supported by the finding that liver microsomes from subjects homozygous for the UGT1A1*28 allele showed significantly lower activity than those from subjects carrying the wild-type UGT1A1 allele. Interestingly, BIBF1202-G was converted to BIBF1202 in HLS9 at 70-fold higher rates than the rates of BIBF1202 glucuronidation. An inhibition study and proteomic correlation analysis suggested that ß-glucuronidase is responsible for hepatic BIBF1202-G deglucuronidation. In conclusion, the major metabolic reactions of nintedanib in the human liver and intestine were quantitatively and thoroughly elucidated. This information could be helpful to understand the inter- and intraindividual variability in the efficacy of nintedanib. SIGNIFICANCE STATEMENT: To our knowledge, this is the first study to characterize the enzymes responsible for each step of nintedanib metabolism in the human body. This study found that ß-glucuronidase may contribute to BIBF1202-G deglucuronidation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteômica , Glucuronosiltransferase/metabolismo , Microssomos Hepáticos/metabolismo , Glucuronídeos/metabolismo , Hidrolases/metabolismo , Glucuronidase/metabolismo , Cinética
3.
Front Physiol ; 13: 825596, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35237179

RESUMO

Cementum resorption, unlike bone resorption, is clinically known to occur only with limited pathological stimuli, such as trauma, orthodontic forces, and large apical periodontitis; however, the molecular mechanisms that control osteoclast formation on the cementum surface remain unclear. In this study, we focused on extracellular vesicles (EVs) secreted by cementoblasts and analyzed their effects on osteoclast differentiation. EVs were extracted from the conditioned medium (CM) of the mouse cementoblast cell line OCCM-30. Transmission electron microscopy (TEM) analysis confirmed the presence of EVs with a diameter of approximately 50-200 nm. The effect of the EVs on osteoclast differentiation was examined using the mouse osteoclast progenitor cell line RAW 264.7 with recombinant receptor activator of nuclear factor (NF)-κB ligand (rRANKL) stimulation. EVs enhanced the formation of tartrate-resistant acid phosphatase (TRAP) activity-positive cells upon rRANKL stimulation. EVs also enhanced the induction of osteoclast-associated gene and protein expression in this condition, as determined by real-time PCR and Western blotting, respectively. On the other hand, no enhancing effect of EVs was observed without rRANKL stimulation. A Western blot analysis revealed no expression of receptor activator of NF-κB ligand (RANKL) in EVs themselves. The effect on rRANKL-induced osteoclast differentiation was examined using the CM of cementoblasts in terms of TRAP activity-positive cell formation and osteoclast-associated gene expression. The conditioned medium partly inhibited rRANKL-induced osteoclast differentiation and almost completely suppressed its enhancing effect by EVs. These results indicate that cementoblasts secreted EVs, which enhanced RANKL-induced osteoclast differentiation, and simultaneously produced soluble factors that neutralized this enhancing effect of EVs, implicating this balance in the regulation of cementum absorption. A more detailed understanding of this crosstalk between cementoblasts and osteoclasts will contribute to the development of new therapies for pathological root resorption.

4.
Xenobiotica ; 51(12): 1352-1359, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34779706

RESUMO

Pirfenidone is a first-line drug for the treatment of idiopathic pulmonary fibrosis. The primary metabolic pathways of pirfenidone in humans are 5-hydroxylation and subsequent oxidation to 5-carboxylpirfenidone. The aims of this study were to determine the cytochrome P450 isoforms responsible for pirfenidone 5-hydroxylation and to evaluate their contributions in human liver microsomes (HLM).Among the recombinant P450 isoforms, CYP1A2, CYP2D6, CYP2C19, CYP2A6, and CYP2B6 were shown to catalyse the 5-hydroxylation of pirfenidone. Pirfenidone 5-hydroxylase activity by HLM was inhibited by α-naphthoflavone (by 45%), 8-methoxypsolaren (by 84%), tranylcypromine (by 53%), and quinidine (by 15%), which are CYP1A2, CYP1A2/CYP2A6/CYP2C19, CYP2A6/CYP2C19, and CYP2D6 inhibitors, respectively.In 17 individual HLM donors, pirfenidone 5-hydroxylase activity was significantly correlated with phenacetin O-deethylase (r = 0.89, P < 0.001) and S-mephenytoin 4'-hydroxylase activities (r = 0.51, P < 0.05), which are CYP1A2 and CYP2C19 marker activities, respectively.By using the relative activity factors, the contributions of CYP1A2, CYP2C19, and CYP2D6 to pirfenidone 5-hydroxylation in the human liver were 72.8%, 11.8%, and 8.9%, respectively.In conclusion, we clearly demonstrated the predominant P450 involved in pirfenidone 5-hydroxylation in the human liver is CYP1A2, with CYP2C19 and CYP2D6 playing a minor role.


Assuntos
Citocromos , Catálise , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromos/metabolismo , Humanos , Hidroxilação , Fígado/metabolismo , Microssomos Hepáticos/metabolismo , Piridonas
5.
Life Sci ; 284: 119896, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34450168

RESUMO

AIM: Abiraterone acetate for metastatic castration-resistant prostate cancer is an acetylated prodrug to be hydrolyzed to abiraterone. Abiraterone acetate is known to be hydrolyzed by pancreatic cholesterol esterase secreted into the intestinal lumen. This study aimed to investigate the possibility that arylacetamide deacetylase (AADAC) expressed in enterocytes contributes to the hydrolysis of abiraterone acetate based on its substrate preference. MATERIALS AND METHODS: Abiraterone acetate hydrolase activity was measured using human intestinal (HIM) and liver microsomes (HLM) as well as recombinant AADAC. Correlation analysis between activity and AADAC expression was performed in 14 individual HIMs. The in vivo pharmacokinetics of abiraterone acetate was examined using wild-type and Aadac knockout mice administered abiraterone acetate with or without orlistat, a pancreatic cholesterol esterase inhibitor. KEY FINDINGS: Recombinant AADAC showed abiraterone acetate hydrolase activity with similar Km value to HIM and HLM. The positive correlation between activity and AADAC levels in individual HIMs supported the responsibility of AADAC for abiraterone acetate hydrolysis. The area under the plasma concentration-time curve (AUC) of abiraterone after oral administration of abiraterone acetate in Aadac knockout mice was 38% lower than that in wild-type mice. The involvement of pancreatic cholesterol esterase in abiraterone formation was revealed by the decreased AUC of abiraterone by coadministration of orlistat. Orlistat potently inhibited AADAC, implying its potential as a perpetrator of drug-drug interactions. SIGNIFICANCE: AADAC is responsible for the hydrolysis of abiraterone acetate in the intestine and liver, suggesting that concomitant use of abiraterone acetate and drugs potently inhibiting AADAC should be avoided.


Assuntos
Acetato de Abiraterona/metabolismo , Hidrolases de Éster Carboxílico/metabolismo , Acetato de Abiraterona/sangue , Acetato de Abiraterona/química , Acetato de Abiraterona/farmacocinética , Adolescente , Adulto , Idoso , Androstenos/sangue , Animais , Carboxilesterase/metabolismo , Feminino , Humanos , Hidrólise , Concentração Inibidora 50 , Intestinos/efeitos dos fármacos , Cinética , Masculino , Camundongos Knockout , Microssomos Hepáticos/metabolismo , Pessoa de Meia-Idade , Orlistate/administração & dosagem , Orlistate/farmacologia , Proteínas Recombinantes/metabolismo
6.
Anat Sci Int ; 91(2): 196-206, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25957016

RESUMO

We investigated the immunohistochemical localization of tenascin-C in 8-week-old rat periodontal ligaments. Tenascin-C immunoreactivity was detected in zones along with cementum and alveolar bone, and more intensely on the resorption surface of alveolar bone than on the formation surface. On the resorbing surface, tenascin-C immunoreactivity was detected in Howship's lacunae without osteoclasts, and in the interfibrous space of the periodontal ligaments, indicating that this molecule works as an adhesion molecule between bone and fibers of periodontal ligaments. Upon experimental tooth movement by inserting elastic bands (Waldo method), the physiological resorption surface of alveolar bone under compressive force showed enhanced bone resorption and enhanced tenascin-C immunoreactivity. However, on the physiological bone formation surface under compressive force, bone resorption was seen only occasionally, and no enhanced tenascin-C immunoreactivity was noted. In an experiment involving excessive occlusal loading to rat molars, transient bone resorption occurred within interradicular septa, but no enhanced tenascin-C immunoreactivity was seen in the periodontal ligaments. These results indicate that tenascin-C works effectively on the bone resorbing surface of physiological alveolar bone remodeling sites, rather than on the non-physiological transient bone resorbing surface. Fibronectin immunoreactivity was distributed evenly in the periodontal ligaments under experimental conditions. Co-localization of tenascin-C and fibronectin immunoreactivity was observed in many regions, but mutually exclusive expression patterns were also seen in some regions, indicating that fibronectin might not be directly involved in alveolar bone remodeling, but may play a role via interaction with tenascin-C.


Assuntos
Processo Alveolar/fisiologia , Remodelação Óssea/fisiologia , Ligamento Periodontal/metabolismo , Tenascina/metabolismo , Tenascina/fisiologia , Animais , Fibronectinas/metabolismo , Fibronectinas/fisiologia , Imuno-Histoquímica , Masculino , Ratos Wistar
7.
Horm Behav ; 74: 149-56, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26122288

RESUMO

This article is part of a Special Issue "Estradiol and cognition". Estradiol (E2) is locally synthesized within the hippocampus and the gonads. Rapid modulation of hippocampal synaptic plasticity by E2 is essential for synaptic regulation. The molecular mechanisms of modulation through the synaptic estrogen receptor (ER) and its downstream signaling, however, are largely unknown in the dentate gyrus (DG). We investigated the E2-induced modulation of dendritic spines in male adult rat hippocampal slices by imaging Lucifer Yellow-injected DG granule cells. Treatments with 1 nM E2 increased the density of spines by approximately 1.4-fold within 2h. Spine head diameter analysis showed that the density of middle-head spines (0.4-0.5 µm) was significantly increased. The E2-induced spine density increase was suppressed by blocking Erk MAPK, PKA, PKC and LIMK. These suppressive effects by kinase inhibitors are not non-specific ones because the GSK-3ß antagonist did not inhibit E2-induced spine increase. The ER antagonist ICI 182,780 also blocked the E2-induced spine increase. Taken together, these results suggest that E2 rapidly increases the density of spines through kinase networks that are driven by synaptic ER.


Assuntos
Espinhas Dendríticas/fisiologia , Giro Denteado/citologia , Estradiol/fisiologia , Proteínas Quinases/fisiologia , Animais , Contagem de Células , Espinhas Dendríticas/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Estradiol/análogos & derivados , Estradiol/farmacologia , Antagonistas do Receptor de Estrogênio/farmacologia , Fulvestranto , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Ratos , Ratos Wistar
8.
Photosynth Res ; 126(2-3): 249-59, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25896488

RESUMO

The light-harvesting chlorophyll a/b binding protein complex of photosystem II (LHCII) is the main antenna complex of photosystem II (PSII). Plants change their LHCII content depending on the light environment. Under high-light conditions, the content of LHCII should decrease because over-excitation damages the photosystem. Chlorophyll b is indispensable for accumulating LHCII, and chlorophyll b degradation induces LHCII degradation. Chlorophyll b degradation is initiated by chlorophyll b reductase (CBR). In land plants, NON-YELLOW COLORING 1 (NYC1) and NYC1-Like (NOL) are isozymes of CBR. We analyzed these mutants to determine their functions under high-light conditions. During high-light treatment, the chlorophyll a/b ratio was stable in the wild-type (WT) and nol plants, and the LHCII content decreased in WT plants. The chlorophyll a/b ratio decreased in the nyc1 and nyc1/nol plants, and a substantial degree of LHCII was retained in nyc1/nol plants after the high-light treatment. These results demonstrate that NYC1 degrades the chlorophyll b on LHCII under high-light conditions, thus decreasing the LHCII content. After the high-light treatment, the maximum quantum efficiency of the PSII photochemistry was lower in nyc1 and nyc1/nol plants than in WT and nol plants. A larger light-harvesting system would damage PSII in nyc1 and nyc1/nol plants. The fluorescence spectroscopy of the leaves indicated that photosystem I was also damaged by the excess LHCII in nyc1/nol plants. These observations suggest that chlorophyll b degradation by NYC1 is the initial reaction for the optimization of the light-harvesting capacity under high-light conditions.


Assuntos
Oxirredutases do Álcool/metabolismo , Proteínas de Arabidopsis/metabolismo , Arabidopsis/enzimologia , Clorofila/metabolismo , Proteínas de Membrana/metabolismo , Oxirredutases/metabolismo , Arabidopsis/genética , Arabidopsis/efeitos da radiação , Proteínas de Arabidopsis/genética , Clorofila/química , Luz , Complexos de Proteínas Captadores de Luz/metabolismo , Proteínas de Membrana/genética , Oxirredutases/genética , Complexo de Proteína do Fotossistema I/metabolismo , Complexo de Proteína do Fotossistema II/metabolismo , Folhas de Planta/metabolismo , Folhas de Planta/efeitos da radiação
9.
Brain Res ; 1621: 147-61, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-25595055

RESUMO

Estradiol (E2) is locally synthesized within the hippocampus in addition to the gonads. Rapid modulation of hippocampal synaptic plasticity by E2 is essential for synaptic regulation. Molecular mechanisms of modulation through synaptic estrogen receptor (ER) and its downstream signaling, however, have been still unknown. We investigated induction of LTP by the presence of E2 upon weak theta burst stimulation (weak-TBS) in CA1 region of adult male hippocampus. Since only weak-TBS did not induce full-LTP, weak-TBS was sub-threshold stimulation. We observed LTP induction by the presence of E2, after incubation of hippocampal slices with 10nM E2 for 30 min, upon weak-TBS. This E2-induced LTP was blocked by ICI, an ER antagonist. This E2-LTP induction was inhibited by blocking Erk MAPK, PKA, PKC, PI3K, NR2B and CaMKII, individually, suggesting that Erk MAPK, PKA, PKC, PI3K and CaMKII may be involved in downstream signaling for activation of NMDA receptors. Interestingly, dihydrotestosterone suppressed the E2-LTP. We also investigated rapid changes of dendritic spines (=postsynapses) in response to E2, using hippocampal slices from adult male rats. We found 1nM E2 increased the density of spines by approximately 1.3-fold within 2h by imaging Lucifer Yellow-injected CA1 pyramidal neurons. The E2-induced spine increase was blocked by ICI. The increase in spines was suppressed by blocking PI3K, Erk MAPK, p38 MAPK, PKA, PKC, LIMK, CaMKII or calcineurin, individually. On the other hand, blocking JNK did not inhibit the E2-induced spine increase. Taken together, these results suggest that E2 rapidly induced LTP and also increased the spine density through kinase networks that are driven by synaptic ER. This article is part of a Special Issue entitled SI: Brain and Memory.


Assuntos
Região CA1 Hipocampal/fisiologia , Espinhas Dendríticas/fisiologia , Estradiol/fisiologia , Potenciação de Longa Duração , Proteínas Quinases/metabolismo , Células Piramidais/fisiologia , Transdução de Sinais , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Estimulação Elétrica , Estradiol/farmacologia , Quinases Lim/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases , Masculino , Fosfatidilinositol 3-Quinase/metabolismo , Proteína Quinase C/metabolismo , Células Piramidais/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo
10.
Cereb Cortex ; 21(12): 2704-11, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21527787

RESUMO

Accurate 3D determination of postsynaptic structures is essential to our understanding memory-related function and pathology in neurons. However, current methods of spine analysis require time-consuming and labor-intensive manual spine identification in large image data sets. Therefore, a realistic implementation of algorithm is necessary to replace manual identification. Here, we describe a new method for the automated detection of spines and dendrites based on analysis of geometrical features. Our "Spiso-3D" software carries out automated dendrite reconstruction and spine detection using both eigenvalue images and information of brightness, avoiding detection of pseudo-spines. To demonstrate the potential application of Spiso-3D automated analysis, we distinguished the rapid effects of androgen and estrogen on rapid modulation of spine head diameter in the hippocampus. These findings advance our understanding of neurotrophic function of brain sex steroids. Our method is expected to be valuable to analyze vast amounts of dendritic spines in neurons in the mammalian cerebral cortex.


Assuntos
Automação Laboratorial/métodos , Espinhas Dendríticas , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Software , Algoritmos , Androgênios/farmacologia , Animais , Espinhas Dendríticas/efeitos dos fármacos , Estrogênios/farmacologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Masculino , Microscopia Confocal , Ratos , Ratos Wistar
11.
Biochem Biophys Res Commun ; 381(4): 728-32, 2009 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-19254689

RESUMO

Modulation of hippocampal synaptic plasticity by androgen has been attracting much attention. Thorns of thorny excrescences of CA3 hippocampal neurons are post-synaptic regions whose presynaptic partners are mossy fiber terminals. Here we demonstrated rapid effects of dihydrotestosterone (DHT) and testosterone (T) on the density of thorns, by imaging Lucifer Yellow-injected neurons in adult male rat hippocampal slices. The application of 10nM DHT or T induced rapid increase in the density of thorns within 2h. The androgen-mediated increase was suppressed by blocking several kinases, such as Erk MAPK, p38 MAPK, PKC, and CaMKII. On the other hand, PKA, PI3K were not involved in the signaling of thorn-genesis. The increase in the thorn density by androgen was also blocked by the inhibitor of classical androgen receptor. Almost no difference was observed between DHT and T in the effect on the thorn density. We observed that the androgen-induced thorn-genesis is opposite to estrogen-induced thorn-degeneration.


Assuntos
Androgênios/fisiologia , Dendritos/fisiologia , Hipocampo/fisiologia , Androgênios/farmacologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dendritos/efeitos dos fármacos , Di-Hidrotestosterona/metabolismo , Di-Hidrotestosterona/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Wistar , Testosterona/farmacologia , Testosterona/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Gan To Kagaku Ryoho ; 30 Suppl 1: 149-52, 2003 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-14708322

RESUMO

The home drip infusion is a stressful procedure for both patients and families under HPN at home. Effective and reliable guidance for drip infusion management should be provided while patients are still at the hospital to realize reliable home care. We revised the HPN Guidance Manual and report the process in this article. We revised the manual according to the principles that "the guidance is subdivided into 3 steps so that the contents of the guidance can be adjusted for individual patients", that "a lot of photos and illustrations for frequently used 2 models are placed" and that "a video is prepared to make the most of the impact motion pictures can give". We want to use the manual in future clinical practices.


Assuntos
Folhetos , Nutrição Parenteral no Domicílio , Educação de Pacientes como Assunto/métodos , Serviços de Assistência Domiciliar , Humanos
13.
Gan To Kagaku Ryoho ; 30(1 Suppl): 149-52, 2003 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-15311789

RESUMO

The home drip infusion is a stressful procedure for both patients and families under HPN at home. Effective and reliable guidance for drip infusion management should be provided while patients are still at the hospital to realize reliable home care. We revised the HPN Guidance Manual and report the process in this article. We revised the manual according to the principles that "the guidance is subdivided into 3 steps so that the contents of the guidance can be adjusted for individual patients", that "a lot of photos and illustrations for frequently used 2 models are placed" and that "a video is prepared to make the most of the impact motion pictures can give". We want to use the manual in future clinical practices.


Assuntos
Serviços de Assistência Domiciliar , Folhetos , Nutrição Parenteral no Domicílio , Educação de Pacientes como Assunto , Humanos , Alta do Paciente , Ensino
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