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BACKGROUND: Clarithromycin (CAM) resistance is a major contributor to the failure to eradicate Helicobacter pylori (H. pylori). The mixed-infection ratio of CAM-susceptible and CAM-resistant H. pylori strains differs among individuals. Pyrosequencing analysis can be used to quantify gene mutations at position each 2142 and 2143 of the H. pylori 23S rRNA gene in intragastric fluid samples. Herein, we aimed to clarify the impact of the rate of mixed infection with CAM-susceptible and CAM-resistant H. pylori strains on the success rate of CAM-containing eradication therapy. MATERIALS AND METHODS: Sixty-four H. pylori-positive participants who received CAM-based eradication therapy, also comprising vonoprazan and amoxicillin, were enrolled in this prospective cohort study. Biopsy and intragastric fluid samples were collected during esophagogastroduodenoscopy. H. pylori culture and CAM-susceptibility tests were performed on the biopsy samples, and real-time PCR and pyrosequencing analyses were performed on the intragastric fluid samples. The mutation rates and eradication success rates were compared. RESULTS: The overall CAM-based eradication success rate was 84% (54/64): 62% (13/21) for CAM-resistant strains, and 95% (39/41) for CAM-sensitive strains. When the mutation rate of the 23S rRNA gene was 20% or lower for both positions (2142 and 2143), the eradication success rate was 90% or more. However, when the mutation rate was 20% or higher, the eradication success rate was lower (60%). CONCLUSIONS: The mutation rate of the CAM-resistance gene was related to the success of eradication therapy, as determined via pyrosequencing analysis.
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Coinfecção , Infecções por Helicobacter , Helicobacter pylori , Humanos , Claritromicina/farmacologia , Claritromicina/uso terapêutico , Helicobacter pylori/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Estudos Prospectivos , Coinfecção/tratamento farmacológico , Farmacorresistência Bacteriana , RNA Ribossômico 23S/genéticaRESUMO
Sphingolipidoses are inherited metabolic disorders associated with glycosphingolipids accumulation, neurodegeneration, and neuroinflammation leading to severe neurological symptoms. Lysoglycosphingolipids (lysoGSLs), also known to accumulate in the tissues of sphingolipidosis patients, exhibit cytotoxicity. LysoGSLs are the possible pathogenic cause, but the mechanisms are still unknown in detail. Here, we first show that lysoGSLs are potential inhibitors of phosphoinositide 3-kinase (PI3K) to reduce cell survival signaling. We found that phosphorylated Akt was commonly reduced in fibroblasts from patients with sphingolipidoses, including GM1/GM2 gangliosidoses and Gaucher's disease, suggesting the contribution of lysoGSLs to the pathogenesis. LysoGSLs caused cell death and decreased the level of phosphorylated Akt as in the patient fibroblasts. Extracellularly administered lysoGM1 permeated the cell membrane to diffusely distribute in the cytoplasm. LysoGM1 and lysoGM2 also inhibited the production of phosphatidylinositol-(3,4,5)-triphosphate and the translocation of Akt from the cytoplasm to the plasma membrane. We also predicted that lysoGSLs could directly bind to the catalytic domain of PI3K by in silico docking study, suggesting that lysoGSLs could inhibit PI3K by directly interacting with PI3K in the cytoplasm. Furthermore, we revealed that the increment of lysoGSLs amounts in the brain of sphingolipidosis model mice correlated with the neurodegenerative progression. Our findings suggest that the down-regulation of PI3K/Akt signaling by direct interaction of lysoGSLs with PI3K in the brains is a neurodegenerative mechanism in sphingolipidoses. Moreover, we could propose the intracellular PI3K activation or inhibition of lysoGSLs biosynthesis as novel therapeutic approaches for sphingolipidoses because lysoGSLs should be cell death mediators by directly inhibiting PI3K, especially in neurons.
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Fosfatidilinositol 3-Quinases , Esfingolipidoses , Humanos , Camundongos , Animais , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinase , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esfingolipidoses/metabolismo , Morte CelularRESUMO
Lysosomal storage disorders (LSDs) are inherited metabolic diseases caused by genetic defects in lysosomal enzymes or related factors. LSDs are associated with excessive accumulation of natural substrates in lysosomes leading to central nervous system and peripheral tissue damage. Abnormal autophagy is also involved in pathogenesis, although the underlying mechanisms remain unclear. We demonstrated that impairment of lysosome-autophagosome fusion is due to suppressed endocytosis in LSDs. The fusion was reduced in several LSD cells and the brains of LSD model mice, suggesting that the completion of autophagy is suppressed by the accumulation of substrates. In this brain, the expression of the soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins, VAMP8 and Syntaxin7, was decreased on the lysosomal surface but not intracellular. This aberrant autophagy preceded the development of pathological phenotypes in LSD-model mice. Furthermore, the enzyme deficiency leading to the substrate accumulation could suppress endocytosis, and the inhibited endocytosis decreased SNARE proteins localized on lysosomes. These findings suggest that the shortage of SNARE proteins on lysosomes is one of the reasons for the impairment of lysosome-autophagosome fusion in LSD cells. Defects in lysosomal enzyme activity suppress endocytosis and decrease the supply of intracellular SNARE proteins recruited to lysosomes. This shortage of lysosomal SNARE proteins impairs lysosome-autophagosome fusion in lysosomal storage disorders.
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Doenças por Armazenamento dos Lisossomos , Proteínas SNARE , Animais , Camundongos , Autofagia/fisiologia , Endocitose , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/metabolismo , Lisossomos/metabolismo , Proteínas SNARE/metabolismoRESUMO
BACKGROUND: Although there are many Helicobacter pylori (H. pylori) diagnostic methods, the culture and antibiotic susceptibility test is an important method for selecting the most effective H. pylori eradication regimen. However, this diagnostic method is complicated and takes several days; therefore, the development of a rapid and simple diagnostic method is required. Eradication failure due to clarithromycin (CAM) resistance should also be considered. In this study, we report the clinical evaluation of point-of-care testing (POCT) kit using intragastric fluid, a novel kit for detecting H. pylori and CAM resistance. MATERIALS AND METHODS: The study participants were 143 patients suspected of H. pylori infection and had an endoscopic examination. The novel diagnostic kit diagnosed H. pylori infection and CAM resistance-associated mutation using intragastric fluid. To diagnose H. pylori infection, the relationship between the diagnostic kit and conventional diagnostic methods (urea breath test, stool antigen test, culture test, and real-time polymerase chain reaction [PCR]) was evaluated. For CAM resistance-associated mutation detection, the concordance between the diagnostic kit and antibiotic susceptibility test was evaluated. RESULTS: The diagnosis of H. pylori infection with the novel molecular diagnostic kit using intragastric fluid showed significant relationship with conventional diagnostic methods. Especially when the culture was control, the sensitivity was 100% (67/67), the specificity was 95.9% (71/74), and the overall concordance was 97.9% (138/141). The detection of CAM resistance-associated mutations had a concordance rate of 97.0% (65/67) when compared with the antibiotic susceptibility test. CONCLUSIONS: The H. pylori molecular POCT kit uses intragastric fluid as a sample and can diagnose H. pylori infection and detect CAM resistance-associated mutations within an hour. This novel kit is expected to prove useful in selecting the most effective eradication regimen for H. pylori.
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Infecções por Helicobacter , Helicobacter pylori , Humanos , Helicobacter pylori/genética , Claritromicina/farmacologia , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Farmacorresistência Bacteriana/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes de Sensibilidade MicrobianaRESUMO
PD-L2, which has been identified as a PD-1 ligand, is specifically expressed in dendritic cells (DCs) and macrophages. The transcription factors that determine the cell type-specific expression of PD-L2 are largely unknown, although PD-1 and its ligands, which have been shown to play important roles in T cell suppression, have been vigorously analyzed in the field of cancer immunology. To reveal the mechanism by which Pdcd1lg2 gene expression is regulated, we focused on DCs, which play key roles in innate and acquired immunity. The knockdown of the hematopoietic cell-specific transcription factors PU.1 and IRF4 decreased PD-L2 expression in GM-CSF-induced mouse bone marrow-derived DCs. Chromatin immunoprecipitation assays, luciferase assays, and electrophoretic mobility shift assays demonstrated that PU.1 and IRF4 bound directly to the Pdcd1lg2 gene via an Ets-IRF composite element sequence and coordinately transactivated the Pdcd1lg2 gene. Furthermore, PU.1 knockdown reduced the histone acetylation of the Pdcd1lg2 gene. The knockdown of the typical histone acetyltransferase p300, which has been reported to interact with PU.1, decreased the expression and H3K27 acetylation of the Pdcd1lg2 gene. GM-CSF stimulation upregulated the Pdcd1lg2 gene expression, which was accompanied by an increase in PU.1 binding and histone acetylation in Flt3L-generated mouse bone marrow-derived DCs. The involvement of PU.1, IRF4, and p300 were also observed in mouse splenic DCs. Overall, these results indicate that PU.1 positively regulates Pdcd1lg2 gene expression as a transactivator and an epigenetic regulator in DCs.
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Células Dendríticas/imunologia , Epigênese Genética/imunologia , Fatores Reguladores de Interferon/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas/imunologia , Transativadores/imunologia , Ativação Transcricional/imunologia , Animais , Células Dendríticas/citologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB CRESUMO
We propose, to the best of our knowledge, the world's first system capable of fast calculating computer-generated holograms (CGHs) from a large-scale outdoor sports scene captured with multiple RGB cameras. In the system, we introduce a fast calculation method focusing on hidden region continuity (HRC) that frequently appears in a point cloud of a 3D sports scene generated from free-viewpoint video technology. The experimental results show that the calculation time of the proposed HRC method is five to 10 times faster than that of the point-based method, which is one of the common CGH calculation methods.
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BACKGROUND. Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, partly because of challenges in early diagnosis. However, the prognosis for earlier stages (carcinoma in situ or category T1a invasive carcinoma) is relatively favorable. OBJECTIVE. The purpose of this study was to investigate findings of an earlier diagnosis of PDAC on CT examinations performed at least 1 year before the diagnosis of clinical stage I PDAC. METHODS. This retrospective study included 103 patients with clinical stage I PDAC and a CT examination performed at least 1 year before the CT examination that detected PDAC, as well as 103 control patients without PDAC on CT examinations separated by at least 10 years. The frequency and temporal characteristics of focal pancreatic abnormalities (pancreatic mass, main pancreatic duct [MPD] change, parenchymal atrophy, faint parenchymal enhancement, cyst, and parenchymal calcification) seen on CT examinations conducted before diagnosis (prediagnostic CT) were determined. RESULTS. A focal pancreatic abnormality was present on the most recent prediagnostic CT examination in 55/103 (53.4%) patients with PDAC versus 21/103 (20.4%) control patients (p < .001). In patients with PDAC, the most common focal abnormalities on prediagnostic CT were atrophy (39/103, 37.9%), faint enhancement (17/65, 26.2%), and MPD change (14/103, 13.6%), which were all more frequent in patients with PDAC than in control patients (p < .05). In 54/55 (98.2%) patients with PDAC, the PDAC corresponded to the site of a focal abnormality (exact location or the abnormality's upstream or downstream edge) on prediagnostic CT. Frequency of focal abnormalities decreased with increasing time before CT that detected PDAC (> 1 to ≤ 2 years before diagnosis, 64.9%; > 2 to ≤ 3 years, 49.2%; > 3 to ≤ 5 years, 41.8%; > 5 to ≤ 7 years, 29.7%; > 7 to ≤ 10 years, 18.5%; more than 10 years, 0%). Mean duration from the finding's initial appearance to diagnosis of PDAC was 4.6 years for atrophy, 3.3 years for faint enhancement, and 1.1 years for MPD change. CONCLUSION. Most patients with clinical stage I PDAC showed focal pancreatic abnormalities on CT performed at least 1 year before diagnosis. Focal MPD change exhibited the shortest duration from its development to subsequent diagnosis, whereas atrophy and faint enhancement exhibited a relatively prolonged course. CLINICAL IMPACT. These findings could facilitate earlier PDAC diagnosis and thus improve prognosis.
Assuntos
Adenocarcinoma/diagnóstico por imagem , Carcinoma Ductal Pancreático/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/patologia , Estudos de Casos e Controles , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Ductos Pancreáticos/diagnóstico por imagem , Ductos Pancreáticos/patologia , Neoplasias Pancreáticas/patologia , Estudos RetrospectivosRESUMO
Augmented reality (AR) using a holographic head-mounted display has been attracting a great deal of attention. In the AR system, computer-generated holograms (CGHs) are calculated and displayed on an electronic display. However, the time required for making CGHs is very long. Here, we propose a fast calculation method for arbitrary viewpoint movements in holographic AR systems. The calculation uses a Fourier transform optical system to enlarge the visual field of electroholography. In experiments, the generation time of the proposed method was approximately twice as fast as that of the conventional method. Furthermore, the quality of the CGHs generated by our method was sufficiently high.
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Computer generated hologram (CGH) animations can be made by switching many CGHs on an electronic display. Some fast calculation methods for CGH animations have been proposed, but one for viewpoint movement has not been proposed. Therefore, we designed a fast calculation method of CGH animations for viewpoint parallel shifts and rotation. A Fourier transform optical system was adopted to expand the viewing angle. The results of experiments were that the calculation time of our method was over 6 times faster than that of the conventional method. Furthermore, the degradation in CGH animation quality was found to be sufficiently small.
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Precise structure switching between all of the three forms of three-state nanomechanical DNA origami devices has been accomplished. A nanomechanical DNA origami device called DNA origami pliers, which consists of two levers of 170-nm long, 20-nm wide, and 2-nm thick connected at a Holliday-junction fulcrum, takes three conformations: closed parallel, closed antiparallel, and open cross forms. They were previously applied to construct detection systems for biomolecules in single-molecular resolution by observing the structure switching between cross form and one of the other two forms under atomic force microscope (AFM). We redesigned DNA origami pliers in this study to let them freely switch between all of the three states including parallel-antiparallel direct switching without taking cross form. By the addition of appropriate switcher strands to the solution, hybridization and dehybridization of particular binder strands that fix the levers into predetermined state were selectively triggered as programmed in their sequence. Circuit structure switching through all of the three states in both of the two opposite direction was even successful with the new design.
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DNA de Cadeia Simples/química , DNA Viral/química , Nanoestruturas/química , Bacteriófago M13/genética , DNA Cruciforme/química , DNA Cruciforme/ultraestrutura , DNA de Cadeia Simples/ultraestrutura , DNA Viral/ultraestrutura , Fenômenos Mecânicos , Microscopia de Força Atômica , Nanoestruturas/ultraestruturaRESUMO
Single-molecule pH sensors have been developed by utilizing molecular imaging of pH-responsive shape transition of nanomechanical DNA origami devices with atomic force microscopy (AFM). Short DNA fragments that can form i-motifs were introduced to nanomechanical DNA origami devices with pliers-like shape (DNA Origami Pliers), which consist of two levers of 170-nm long and 20-nm wide connected at a Holliday-junction fulcrum. DNA Origami Pliers can be observed as in three distinct forms; cross, antiparallel and parallel forms, and cross form is the dominant species when no additional interaction is introduced to DNA Origami Pliers. Introduction of nine pairs of 12-mer sequence (5'-AACCCCAACCCC-3'), which dimerize into i-motif quadruplexes upon protonation of cytosine, drives transition of DNA Origami Pliers from open cross form into closed parallel form under acidic conditions. Such pH-dependent transition was clearly imaged on mica in molecular resolution by AFM, showing potential application of the system to single-molecular pH sensors.
Assuntos
Técnicas Biossensoriais/métodos , DNA/isolamento & purificação , Nanoestruturas/química , Nanotecnologia , DNA/química , Concentração de Íons de Hidrogênio , Microscopia de Força Atômica , Conformação de Ácido NucleicoRESUMO
Background: We developed a technique to preserve the entire nasolacrimal duct and inferior turbinate, by swinging the nasolacrimal duct upward and the inferior turbinate backward; that is, a nasolacrimal duct and inferior turbinate swing technique for sinonasal inverted papilloma of the maxillary sinus. In this study, we evaluated the long-term results of this technique. Methods: A retrospective analysis was performed on the data for 53 consecutive pathologically confirmed inverted papilloma patients who were treated using nasolacrimal duct and inferior turbinate swing technique. The frequency of recurrence, the degree of nasolacrimal duct and inferior turbinate preservation, and the frequency of adverse events were assessed. Results: The median follow-up period was 51 months (mean 62.5 months; range 10-187 months). No cases of recurrence within the maxillary sinus were observed among the cases treated using this technique, whereas three (5.7%) of the 53 cases experienced recurrence in areas other than the maxillary sinus. We could preserve the nasolacrimal duct in all cases. On the other hand, the inferior turbinate was resected during surgery in one case. No epiphora, dacryocystiits, numbness of the cheek, or collapse of the ala of the nose was observed. Conclusion: This nasolacrimal duct and inferior turbinate swing technique method is a safe and effective method for the excision of primary or recurrent inverted papilloma and demonstrates low rates of recurrence and complications.
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Scanning of the mRNA transcript by the preinitiation complex (PIC) requires a panel of eukaryotic initiation factors, which includes eIF1 and eIF1A, the main transducers of stringent AUG selection. eIF1A plays an important role in start codon recognition; however, its molecular contacts with eIF5 are unknown. Using nuclear magnetic resonance, we unveil eIF1A's binding surface on the carboxyl-terminal domain of eIF5 (eIF5-CTD). We validated this interaction by observing that eIF1A does not bind to an eIF5-CTD mutant, altering the revealed eIF1A interaction site. We also found that the interaction between eIF1A and eIF5-CTD is conserved between humans and yeast. Using glutathione S-transferase pull-down assays of purified proteins, we showed that the N-terminal tail (NTT) of eIF1A mediates the interaction with eIF5-CTD and eIF1. Genetic evidence indicates that overexpressing eIF1 or eIF5 suppresses the slow growth phenotype of eIF1A-NTT mutants. These results suggest that the eIF1A-eIF5-CTD interaction during scanning PICs contributes to the maintenance of eIF1 within the open PIC.
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Fator de Iniciação 1 em Eucariotos/metabolismo , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Sequência de Aminoácidos , Fator de Iniciação 1 em Eucariotos/química , Fator de Iniciação 1 em Eucariotos/genética , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Fatores de Iniciação de Peptídeos/química , Fatores de Iniciação de Peptídeos/genética , Ligação Proteica , Biossíntese de Proteínas , Multimerização Proteica , Estrutura Terciária de Proteína , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Alinhamento de Sequência , Fator de Iniciação de Tradução Eucariótico 5ARESUMO
Muscle contraction stimulates thin fiber muscle afferents and evokes reflex sympathoexcitation. In hypertension, this reflex is exaggerated. ANG II, which is elevated in hypertension, has been reported to trigger the production of superoxide and other reactive oxygen species. In the present study, we tested the hypothesis that increased ANG II in hypertension exaggerates skeletal muscle contraction-evoked reflex sympathoexcitation by inducing oxidative stress in the muscle. In rats, subcutaneous infusion of ANG II at 450 ng·kg(-1)·min(-1) for 14 days significantly (P < 0.05) elevated blood pressure compared with sham-operated (sham) rats. Electrically induced 30-s hindlimb muscle contraction in decerebrate rats with hypertension evoked larger renal sympathoexcitatory and pressor responses [+1,173 ± 212 arbitrary units (AU) and +35 ± 5 mmHg, n = 10] compared with sham normotensive rats (+419 ± 103 AU and +13 ± 2 mmHg, n = 11). Tempol, a SOD mimetic, injected intra-arterially into the hindlimb circulation significantly reduced responses in hypertensive rats, whereas this compound had no effect on responses in sham rats. Tiron, another SOD mimetic, also significantly reduced reflex renal sympathetic and pressor responses in a subset of hypertensive rats (n = 10). Generation of muscle superoxide, as evaluated by dihydroethidium staining, was increased in hypertensive rats. RT-PCR and immunoblot experiments showed that mRNA and protein for gp91(phox), a NADPH oxidase subunit, in skeletal muscle tissue were upregulated in hypertensive rats. Taken together, hese results suggest that increased ANG II in hypertension induces oxidative stress in skeletal muscle, thereby exaggerating the muscle reflex.
Assuntos
Angiotensina II , Sistema Cardiovascular/inervação , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Rim/inervação , Contração Muscular , Músculo Esquelético/metabolismo , Estresse Oxidativo , Reflexo , Sistema Nervoso Simpático/fisiopatologia , Sal Dissódico do Ácido 1,2-Di-Hidroxibenzeno-3,5 Dissulfônico/administração & dosagem , Vias Aferentes/fisiopatologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Animais , Antioxidantes/administração & dosagem , Pressão Sanguínea , Western Blotting , Óxidos N-Cíclicos/administração & dosagem , Estado de Descerebração , Modelos Animais de Doenças , Estimulação Elétrica , Frequência Cardíaca , Membro Posterior , Hipertensão/induzido quimicamente , Hipertensão/genética , Injeções Intra-Articulares , Losartan/administração & dosagem , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/inervação , NADPH Oxidase 2 , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Reflexo/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Marcadores de Spin , Superóxidos/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Fatores de TempoRESUMO
The translation factor eIF5 is an important partner of eIF2, directly modulating its function in several critical steps. First, eIF5 binds eIF2/GTP/Met-tRNA(i)(Met) ternary complex (TC), promoting its recruitment to 40S ribosomal subunits. Secondly, its GTPase activating function promotes eIF2 dissociation for ribosomal subunit joining. Finally, eIF5 GDP dissociation inhibition (GDI) activity can antagonize eIF2 reactivation by competing with the eIF2 guanine exchange factor (GEF), eIF2B. The C-terminal domain (CTD) of eIF5, a W2-type HEAT domain, mediates its interaction with eIF2. Here, we characterize a related human protein containing MA3- and W2-type HEAT domains, previously termed BZW2 and renamed here as eIF5-mimic protein 1 (5MP1). Human 5MP1 interacts with eIF2 and eIF3 and inhibits general and gene-specific translation in mammalian systems. We further test whether 5MP1 is a mimic or competitor of the GEF catalytic subunit eIF2Bε or eIF5, using yeast as a model. Our results suggest that 5MP1 interacts with yeast eIF2 and promotes TC formation, but inhibits TC binding to the ribosome. Moreover, 5MP1 is not a GEF but a weak GDI for yeast eIF2. We propose that 5MP1 is a partial mimic and competitor of eIF5, interfering with the key steps by which eIF5 regulates eIF2 function.
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Proteínas de Ligação a DNA/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Fatores de Iniciação em Eucariotos/metabolismo , Regulação da Expressão Gênica , Biossíntese de Proteínas , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Linhagem Celular , Fator de Iniciação 2 em Eucariotos/análise , Fator de Iniciação 2B em Eucariotos/metabolismo , Fator de Iniciação 3 em Eucariotos/metabolismo , Guanosina Difosfato/metabolismo , Células HeLa , Humanos , Camundongos , Mimetismo Molecular , Fatores de Iniciação de Peptídeos/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Ligação a RNA/antagonistas & inibidores , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Fator de Iniciação de Tradução Eucariótico 5ARESUMO
Background: Along with the improved prognosis of patients with congenital heart disease, the associated diverse complications are under scrutiny. Due to various medical restrictions on their upbringing, patients with congenital heart disease often have coexisting mental disorders. However, reports on patients with congenital heart disease and coexisting eating disorders are rare. Here, we report the case of a patient who developed anorexia nervosa (AN) following surgery for Ebstein's anomaly. Case Presentation: A 21-year-old female with Ebstein's anomaly who underwent Fontan surgery was transferred to our institution with suspected AN after >2 years of intermittent stays at a medical hospital for decreased appetite. Initially, she did not desire to lose weight or fear obesity, and we suspected that she was suffering from appetite loss due to a physical condition associated with Fontan circulation. However, the eating disorder pathology gradually became more apparent. Conclusion: Our experience suggests that patients with congenital heart disease are more likely to have a psychological background and physical problems that might contribute to eating disorders than the general population.
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PURPOSE: To quantify bowel motility shown on cine MRI using the classical optical flow algorithm and compare it with balloon-assisted enteroscopy (BAE) findings in patients with Crohn's disease (CD). METHODS: This retrospective study included 29 consecutive patients with CD who had undergone MR enterocolonography (MREC) and BAE between March and May 2017. We developed computer software to present motion vector magnitudes between consecutive cine MR images as bowel motility maps via a classical optical flow algorithm using the Horn-Schunck method. Cine MR images were acquired with a balanced steady-state free precession sequence in the coronal direction to capture small bowel motility. The small bowels were divided into three segments. In total, 63 bowel segments were assessed via BAE and MREC. Motility scores on the maps, simplified MR index of activity (sMaRIA), and MREC score derived from a 5-point MR classification were assessed independently by two radiologists and compared with the CD endoscopic index of severity (CDEIS). Correlations were assessed using Spearman's rank coefficient. The areas under the receiver-operating characteristic curve (AUCs) of motility score for differentiating CDEIS was calculated; a P value < 0.05 was considered statistically significant. RESULTS: Motility score was negatively correlated with CDEIS (r = -0.59 [P < 0.001] and -0.54 [P < 0.001]), and the AUCs of motility scores for detecting CDEIS ≥ 3 were 88.2% and 78.6% for observers 1 and 2, respectively. There were no significant differences in the AUC for detecting CDEIS ≥ 3 and CDEIS ≥ 12 between motility and sMaRIA or MREC score. CONCLUSION: The motility map was feasible for locally quantifying the bowel motility. In addition, the motility score on the map reflected the endoscopic inflammatory activity of each small bowel segment in patients with CD; hence, it could be used as a tool in objectively interpreting cine MREC to predict inflammatory activity in CD.
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Doença de Crohn , Fluxo Óptico , Humanos , Doença de Crohn/diagnóstico por imagem , Doença de Crohn/patologia , Estudos Retrospectivos , Intestino Delgado/diagnóstico por imagem , Imageamento por Ressonância Magnética , Algoritmos , Índice de Gravidade de DoençaRESUMO
Acute iron overload is known to exert deleterious effects in the liver, but detailed pathology has yet to be documented. Here, we report pathological findings in an autopsy case of acute iron toxicity and validation of the findings in mouse experiments. In a 39-year-old woman who intentionally ingested a large amount of sodium ferrous citrate (equivalent to 7.5 g of iron), severe disturbance of consciousness and fulminant hepatic failure rapidly developed. Liver failure was refractory to treatment and the patient died on Day 13. Autopsy revealed almost complete loss of hepatocytes, while bile ducts were spared. To examine the detailed pathologic processes induced by excessive iron, mice were orally administered equivalent doses of ferrous citrate. Plasma aminotransferase levels markedly increased after 6 h, which was preceded by increased plasma iron levels. Hepatocytes were selectively damaged, with more prominent damage in the periportal area. Phosphorylated c-Jun was detected in hepatocyte nuclei after 3 h, which was followed by the appearance of γ-H2AX expression. Hepatocyte injury in mice was associated with the expression of Myc and p53 after 12 and 24 h, respectively. Even at lethal doses, the bile ducts were morphologically intact and fully viable. Our findings indicate that acute iron overload induces hepatocyte-specific liver injury, most likely through hydroxyl radical-mediated DNA damage and subsequent stress responses.
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Introduction: Surgeons' mental workload during endoscopic sinus surgery (ESS) has not been fully evaluated. The assessment was challenging due to the great diversity of each patient's anatomy and the consequence variety of surgical difficulties. In this study, we examined the mental workload of surgeons with various surgical skill levels during ESS under the standardized condition provided by novel-designed 3D sinus models. Materials and methods: Forty-seven participants performed a high-fidelity ESS simulation with 3D-printed sinus models. Surgeons' mental workload was assessed with the national aeronautics and space administration-task load index (NASA-TLX). Associations between the total and subscales score of NASA-TLX and surgical skill index, including the board certification status, the number of experienced ESS cases, and the objective structured assessment of technical skills (OSATS), were analyzed. In addition, 10 registrars repeated the simulation surgery, and their NASA-TLX score was compared before and after the repetitive training. Results: The total NASA-TLX score was significantly associated with OSATS score (p = 0.0001). Primary component analysis classified the surgeons' mental burden into three different categories: (1) the skill-level-dependent factors (temporal demand, effort, and performance), (2) the skill-level-independent factors (mental and physical demand), and (3) frustration. After the repetitive training, the skill-level-dependent factors were alleviated (temporal demand; z = -2.3664, p = 0.0091, effort; z = -2.1704, p = 0.0346, and performance; z = -2.5992, p = 0.0017), the independent factors were increased (mental demand; z = -2.5992, p = 0.0023 and physical demand; z = -2.2509, p = 0.0213), and frustration did not change (p = 0.3625). Conclusion: Some of the mental workload during ESS is associated with surgical skill level and alleviated with repetitive training. However, other aspects remain a burden or could worsen even when surgeons have gained surgical experience. Routine assessment of registrars' mental burdens would be necessary during surgical training to sustain their mental health.