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PURPOSE: To observe vestibular impairment patterns in patients with Ramsay Hunt syndrome with dizziness (RHS_D) and sudden sensorineural hearing loss with dizziness (SSNHL_D) using hierarchical cluster analysis (HCA) to interpret results with possible mechanisms. METHODS: The data of 30 RHS_D and 81 SSNHL_D patients from January 2017 to August 2022 in a single tertiary referral center were retrospectively analyzed. Video head impulse test (vHIT) and vestibular evoked myogenic potential (VEMP) were used for vestibular analysis of peripheral vestibular organs, and the results of vHIT and VEMP were analyzed. HCA was used to analyze vestibular impairment patterns. RESULTS: In RHS_D patients, the lateral semicircular canal (LSCC) was the most impaired semicircular canal (SCC), followed by the anterior semicircular canal (ASCC) and the posterior semicircular canal (PSCC), and the utricle was more impaired than the saccule. In SSNHL_D patients, the PSCC was the most impaired SCC, followed by the LSCC and the ASCC, and the utricle was more impaired than the saccule. In HCA of RHS_D patients, the ASCC and utricle were initially clustered, followed by the LSCC, PSCC and saccule in order. In the HCA of SSNHL_D patients, the PSCC was solely merged and independently clustered. CONCLUSION: There were different patterns of vestibular impairments between RHS_D and SSNHL_D patients. The vestibular analysis and HCA results of SSNHL_D showed tendency of skip lesion, which could be explained by vascular pathophysiology.
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Perda Auditiva Neurossensorial , Perda Auditiva Súbita , Herpes Zoster da Orelha Externa , Potenciais Evocados Miogênicos Vestibulares , Humanos , Tontura , Herpes Zoster da Orelha Externa/complicações , Herpes Zoster da Orelha Externa/diagnóstico , Estudos Retrospectivos , Vertigem , Perda Auditiva Neurossensorial/diagnóstico , Canais Semicirculares , Perda Auditiva Súbita/diagnósticoRESUMO
Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into mature cells of various cell types. Although the differentiation process of MSCs requires lineage-specific transcription factors, the exact molecular mechanism that determines MSCs differentiation is not clearly addressed. Here, we demonstrate a Smad4-Taz axis as a new intrinsic regulator for adipo-osteogenic differentiation of MSCs and show that this function of Smad4 is independent of the transforming growth factor-ß signal. Smad4 directly bound to the Taz protein and facilitated nuclear localization of Taz through its nuclear localization signal. Nuclear retention of Taz by direct binding to Smad4 increased expression of osteogenic genes through enhancing Taz-runt-related transcription factor 2 (Runx2) interactions in the C3H10T1/2 MSC cell line and preosteoblastic MC3T3-E1 cells, whereas it suppressed expression of adipogenic genes through promoting Taz-peroxisome proliferator-activated receptor-γ (PPARγ) interaction in C3H10T1/2 and preadipogenic 3T3-L1 cells. A reciprocal role of the Smad4 in osteogenic and adipogenic differentiation was also observed in human adipose tissue-derived stem cells (hASCs). Consequently, Smad4 depletion in C3H10T1/2 and hASCs reduced nuclear retention of Taz and thus caused the decreased interaction with Runx2 or PPARγ, resulting in delayed osteogenesis or enhanced adipogenesis of the MSC. Therefore, these findings provide insight into a novel function of Smad4 to regulate the balance of MSC lineage commitment through reciprocal targeting of the Taz protein in osteogenic and adipogenic differentiation pathways. Stem Cells 2019;37:368-381.
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Adipogenia , Células-Tronco Mesenquimais/metabolismo , Osteogênese , Transdução de Sinais , Proteína Smad4/metabolismo , Transativadores/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Diferenciação Celular , Linhagem Celular , Humanos , Células-Tronco Mesenquimais/citologia , Camundongos , Proteína Smad4/genética , Transativadores/genética , Proteínas com Motivo de Ligação a PDZ com Coativador TranscricionalRESUMO
p62/sequestosome-1 is a scaffolding protein involved in diverse cellular processes such as autophagy, oxidative stress, cell survival and death. It has been identified to interact with atypical protein kinase Cs (aPKCs), linking these kinases to NF-κB activation by tumor necrosis factor α (TNFα). The diverse functions of p62 are regulated through post-translational modifications of several domains within p62. Among the enzymes that mediate these post-translational modifications, little is known about the deubiquitinating enzymes (DUBs) that remove ubiquitin chains from p62, compared to the E3 ligases involved in p62 ubiquitination. In this study, we first demonstrate a role of ubiquitin-specific protease USP20 in regulating p62 stability in TNFα-mediated NF-κB activation. USP20 specifically binds to p62 and acts as a positive regulator for NF-κB activation by TNFα through deubiquitinating lysine 48 (K48)-linked polyubiquitination, eventually contributing to cell survival. Furthermore, depletion of USP20 disrupts formation of the atypical PKCζ-RIPK1-p62 complex required for TNFα-mediated NF-κB activation and significantly increases the apoptosis induced by TNFα plus cycloheximide or TNFα plus TAK1 inhibitor. These findings strongly suggest that the USP20-p62 axis plays an essential role in NF-κB-mediated cell survival induced by the TNFα-atypical PKCζ signaling pathway.
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Lisina/metabolismo , Proteína Sequestossoma-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitina Tiolesterase/metabolismo , Benzamidas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cicloeximida/farmacologia , Regulação da Expressão Gênica , Células HEK293 , Células HT29 , Células HeLa , Humanos , NF-kappa B/metabolismo , Piperazinas/farmacologia , Proteína Quinase C/metabolismo , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , Piridinas/farmacologia , Pirróis/farmacologia , Proteína Sequestossoma-1/química , Transdução de Sinais , Ubiquitina Tiolesterase/genéticaRESUMO
OBJECTIVES: Clinicians sometimes treat patients with relatively long-duration geotropic direction-changing positional nystagmus (DCPN), without latency. Recently, the concept of a "light cupula" in the lateral canal that reveals persistent geotropic DCPN has been introduced. In the present study, we investigated the immediate and short-term therapeutic findings in long-duration DCPN. DESIGN: The authors prospectively compared the therapeutic efficacy of a canalith-repositioning procedure (CRP) in short- and long-duration geotropic DCPN. RESULTS: In patients with long-duration DCPN, the authors found no immediate therapeutic effect, and the number of patients showing short-term effects (on the next day) was very low compared with the comparable figure among those with short-duration DCPN. In addition, no cases exhibited canal conversion after the CRP. CONCLUSION: Our results suggest that CRP is not useful in patients with long-duration geotropic DCPN, and the pathogenesis of long-duration geotropic DCPN may not originate from free-floating debris but from deflection of the cupula.
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Vertigem Posicional Paroxística Benigna/terapia , Nistagmo Patológico/terapia , Nistagmo Fisiológico , Posicionamento do Paciente/métodos , Canais Semicirculares , Adulto , Idoso , Vertigem Posicional Paroxística Benigna/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nistagmo Patológico/fisiopatologia , Postura , Estudos Prospectivos , Fatores de Tempo , Adulto JovemRESUMO
Several studies have demonstrated that deregulated activation of signal transducer and activator of transcription 3 (STAT3) has been associated with survival, proliferation, chemoresistance and angiogenesis of tumour cells. Thus, inhibition of STAT3 expression could be a potent therapeutic approach for cancer treatment. Using several leukaemia cell lines, the effect of the hydrolysed-catalpol (H-catalpol) and hydrolysed-aucubin (H-aucubin) products on the STAT3 signalling pathway, inhibition of BCR-ABL activation, cellular proliferation and potentiation of imatinib mesylate-induced apoptosis was investigated. We found that iridoid glycosides (catalpol and aucubin) did not exert any cytotoxicity in the tumour cells, whereas both H-catalpol and H-aucubin exhibited significant cytotoxic effects on K562 human myeloid leukaemia cells. Indeed, H-catalpol and H-aucubin down-regulated BCR-ABL phosphorylation and inhibited constitutive STAT3 activation through abrogating upstream JAK2 and c-Src and constitutive STAT5 activation leading to apoptosis through caspase-3 activation. Hydrolysed-catalpol enhanced the apoptosis induced by imatinib mesylate and this correlated with down-regulation of gene products that mediate cell proliferation (cyclin D1), and cell survival (Bcl-2, Bcl-xL and survivin); all known to be regulated by the STAT3. Overall, our results provide novel insight into the role of hydrolysed iridoids in potentially treating leukaemia through the modulation of STAT3 signalling pathway.
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Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Glicosídeos Iridoides/farmacologia , Leucemia Mieloide/patologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Proteína Tirosina Quinase CSK , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Humanos , Mesilato de Imatinib , Glucosídeos Iridoides/química , Glucosídeos Iridoides/farmacologia , Glicosídeos Iridoides/química , Janus Quinase 2/metabolismo , Células K562/efeitos dos fármacos , Fosforilação , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/metabolismoRESUMO
We evaluated the short-term efficacy of Epley, Semont, and sham maneuvers for resolving posterior canal benign paroxysmal positional vertigo (BPPV) in a prospective multicenter randomized double-blind controlled study. Subjects were randomly divided into three groups: Epley (36 patients), Semont (32 patients), and sham (Epley maneuver for the unaffected side, 31 patients). Out of 14 institutes which participated in this study, 5 institutes had previous experience of the Epley but not the Semont maneuver and the other 9 had previous experience of both maneuvers. Each maneuver was repeated twice if there was still positional vertigo or nystagmus on day 0, and the presence of nystagmus and vertigo on positional testing were evaluated immediately, 1 day, and 1 week after treatment. After the first maneuver, the Epley group showed a significantly higher resolution rate of positional nystagmus than the Semont or sham groups (63.9, 37.5, and 38.7%, respectively). After the second maneuver, the resolution rate (83.3%) of the Epley group was significantly higher than that (51.6%) of the sham group. At 1 day and 1 week after treatment, the resolution rate of the Epley group was significantly higher than those of the other groups. Similar results were seen for the resolution of positional vertigo. The Epley maneuver showed persistent resolution rates of positional vertigo and nystagmus without a fatigue phenomenon. The Epley maneuver was significantly more effective per maneuver than Semont or sham maneuvers for the short-term treatment of posterior canal BPPV. The Semont maneuver showed a higher success rate than the sham maneuver, but it was not significantly different.
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Vertigem Posicional Paroxística Benigna/reabilitação , Nistagmo Patológico/reabilitação , Modalidades de Fisioterapia , Adulto , Idoso , Vertigem Posicional Paroxística Benigna/complicações , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nistagmo Patológico/complicações , Resultado do TratamentoRESUMO
OBJECTIVES: The object was to evaluate speech perception improvement through Bluetooth-implemented hearing aids in hearing-impaired adults. METHODS: Thirty subjects with bilateral symmetric moderate sensorineural hearing loss participated in this study. A Bluetooth-implemented hearing aid was fitted unilaterally in all study subjects. Objective speech recognition score and subjective satisfaction were measured with a Bluetooth-implemented hearing aid to replace the acoustic connection from either a cellular phone or a loudspeaker system. In each system, participants were assigned to 4 conditions: wireless speech signal transmission into hearing aid (wireless mode) in quiet or noisy environment and conventional speech signal transmission using external microphone of hearing aid (conventional mode) in quiet or noisy environment. Also, participants completed questionnaires to investigate subjective satisfaction. RESULTS: Both cellular phone and loudspeaker system situation, participants showed improvements in sentence and word recognition scores with wireless mode compared to conventional mode in both quiet and noise conditions (P < .001). Participants also reported subjective improvements, including better sound quality, less noise interference, and better accuracy naturalness, when using the wireless mode (P < .001). CONCLUSIONS: Bluetooth-implemented hearing aids helped to improve subjective and objective speech recognition performances in quiet and noisy environments during the use of electronic audio devices.
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Auxiliares de Audição , Perda Auditiva Bilateral/reabilitação , Perda Auditiva Neurossensorial/reabilitação , Percepção da Fala , Tecnologia sem Fio , Adulto , Idoso , Telefone Celular , Retroalimentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ruído , Satisfação do Paciente , Som , Inteligibilidade da Fala , Televisão , Adulto JovemRESUMO
OBJECTIVE: To evaluate the older adults with chronic dizziness using the Barany Society's presbyvestibulopathy (PVP) diagnostic criteria and to assess the clinical usability of the criteria. STUDY DESIGN: Retrospective study. SETTING: Single tertiary medical center. METHODS: Among a total of 1964 patients aged 60 years or older, 55 patients who had symptoms suitable for the PVP criteria and who underwent all 3 vestibular function tests were analyzed. Of these 55 patients, 13 patients were diagnosed with PVP based on the peripheral vestibular hypofunction criteria; the remaining 42 patients were categorized as patients without PVP. RESULTS: In both patients with PVP and patients without PVP, postural imbalance or unsteadiness was the most frequently reported vestibular symptom. The rotatory chair test contributed the most to the quantitative diagnosis of PVP (6 of 13), followed by the caloric response test (3 of 13) and video head impulse test (vHIT; 2 of 13). When we included the presence of catch-up saccades in addition to the vHIT gain in the diagnostic criteria, 5 patients without PVP were additionally diagnosed with PVP. Furthermore, when accounting for the inclusion of catch-up saccades, patients who experienced recurrent falls demonstrated a significantly higher rate of impairments in the lateral and posterior semicircular canals according to the multivariate analysis. CONCLUSION: Considering the catch-up saccades in addition to vHIT gain seemed to contribute to the diagnosis of PVP and prediction of recurrent fall risks in older adults. Further studies are needed to solidify the diagnostic criteria for PVP.
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Tontura , Testes de Função Vestibular , Humanos , Idoso , Tontura/diagnóstico , Tontura/etiologia , Estudos Retrospectivos , Testes Calóricos , Teste do Impulso da Cabeça , Canais Semicirculares , Reflexo Vestíbulo-Ocular/fisiologiaRESUMO
Growing concerns over poor air quality, especially in urban and industrial regions, have led to increased global demands for advanced air-purification technologies. However, the stability and airborne pollutant control abilities of the available air-purification materials under diverse environmental conditions are limited. Thus, the advanced development of filtration materials that can effectively control different types of pollutants, such as particulate matter (PM) and gaseous pollutants, simultaneously has attracted attention. The zeolitic imidazolate framework (ZIF), a type of porous metal-organic framework (MOF), is a promising material for capturing weakly acidic toxic gases such as SO2 owing to its excellent adsorption performance and high thermal and chemical stability. In this study, we successfully developed an ultrastable necklace-like multifunctional hybrid membrane via the cetyltrimethylammonium bromide-assisted in situ growth of zeolitic imidazolate framework (ZIF)-67 crystals on electrospun Co2+-doped poly(vinylidene fluoride) nanofibers (70 nm) that can be used in different moisture environments to achieve sustainable air-filtration performance. The hybrid nanocomposite membrane demonstrated excellent performance for the simultaneous control of intractable fine PM0.3 (filtration efficiency, 99.461%) and SO2 (adsorption capacity, 1476.5 mg g-1) under different humidity conditions. This study contributes to the optimal synergistic integration of the advanced metal-organic framework (MOF)-nanofiber nanocomposite membranes and can guide the rational design and conceptualization of a facile and novel membrane for various applications in the environmental science and energy fields.
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We here demonstrate that SERTAD1 is an adaptor protein responsible for the regulation of lysine 63 (K63)-linked NLRP3 polyubiquitination by the Cullin1 E3 ubiquitin ligase upon inflammasome activation. SERTAD1 specifically binds to NLRP3 but not to other inflammasome sensors. This endogenous interaction increases after inflammasome activation, interfering with the interaction between NLRP3 and Cullin1. Interleukin (IL)-1ß and IL-18 secretion, as well as the cleavage of gasdermin D, are decreased in SERTAD1 knockout bone-marrow-derived macrophages, together with reduced formation of the NLRP3 inflammasome complex. Additionally, SERTAD1-deficient mice show attenuated severity of monosodium-uric-acid-induced peritonitis and experimental autoimmune encephalomyelitis. Analysis of public datasets indicates that expression of SERTAD1 mRNA is significantly increased in the patients of autoimmune diseases. Thus, our findings uncover a function of SERTAD1 that specifically reduces Cullin1-mediated NLRP3 polyubiquitination via direct binding to NLRP3, eventually acting as a crucial factor to regulate the initiation of NLRP3-mediated inflammasome activation.
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Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Humanos , Camundongos , Inflamassomos/metabolismo , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
OBJECTIVE: To identify the prevalence of and relevant information for video head impulse test (vHIT) abnormality in a large population. STUDY DESIGN: A cross-sectional design. SETTING: Korean National Health and Nutrition Examination Survey, 2021. METHODS: The sample was representative of the Korean population, with 2237 participants aged ≥40 years. A vHIT was performed to evaluate vestibular function. The vestibulo-ocular reflex (VOR) gain and the presence of reproducible catch-up saccades was assessed in a vHIT. Participants also completed questionnaires for demographics, socioeconomic status, and basic information regarding systemic diseases and dizziness and underwent hearing tests with automated pure-tone audiometry. RESULTS: The prevalence of vHIT abnormality was 22.5%, with unilateral (14.3%) being more common than bilateral (8.2%). The prevalence of vHIT abnormality increased significantly with age, with the highest rate observed in individuals aged >70 years (42.5%). Both hearing and VOR gain deteriorated with age, but the patterns of age-related progression were different. While hearing loss (HL) deteriorated gradually and progressively throughout adulthood, VOR gain deterioration was markedly evident after 70 years of age. CONCLUSION: Considering the high prevalence of vHIT abnormality, appropriate social and medical policies are needed to prevent associated injuries and improve patients' quality of life. The distinct age-related changes in HL and objective findings of vestibular dysfunction indicate the need for different approaches to address these social problems in aging countries.
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BACKGROUND: We aimed to investigate the clinical courses and common nystagmus of isolated vertigo patients with vertebrobasilar stroke. METHODS: The patients who presented with isolated acute spontaneous vertigo with spontaneous nystagmus (acute vestibular syndrome) at the Emergency Department were retrospectively analyzed. They were referred to the Otolaryngology Department due to the absence of neurologic signs or even of imaging abnormalities after the initial examination at the Emergency Department. Various clinical features, including presenting symptoms, delayed neurologic signs, the site of infarction, and videonystagmographic (VNG) findings were analyzed. RESULTS: Of the 468 cases of acute vestibular syndrome, 23 (4.9%) cases of radiologically proven vertebrobasilar stroke were identified. Of the 23 patients, 17 (74%) showed aggravation of vertigo or delayed neurologic signs during the admission. In the analysis of VNG, 11 (48%) cases of direction-changing gaze-evoked nystagmus, 7 (30%) cases of fixation failure in the caloric test, 6 (27%) cases of periodic alternating nystagmus, and 4 (17%) cases of atypical head-shaking nystagmus were presented. Stroke occurred in the cerebellum (n=18, 78%), medulla (n=4, 17%), and pons (n=1, 4%). CONCLUSION: In the early stage of vertebrobasilar stroke, an accurate diagnosis was difficult in the Emergency Department even though a radiologic study was performed, but various VNG abnormalities and delayed neurologic signs could help to diagnose whether the origin is central or not.
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Cerebelo/patologia , Nistagmo Patológico/etiologia , Acidente Vascular Cerebral/complicações , Vertigem/etiologia , Idoso , Idoso de 80 Anos ou mais , Testes Calóricos/métodos , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnósticoRESUMO
Congenital middle ear cholesteatoma (CMEC) accounts for 2%-5% of all cases of middle ear cholesteatoma. CMEC is rare and diagnostically challenging; therefore, only a few cases are reported in the literature, and the pathophysiology of this condition remains largely unclear. Currently, epidermoid formation, amniotic fluid contamination, lack of the tympanic ring, and squamous metaplasia are among the mechanisms implicated in the pathogenesis of CMEC; however, no single theory satisfactorily explains the pathophysiology of this disorder. We report a case of CMEC in a young male patient, who showed a symmetric, binaural whitish mass posterior to the anterosuperior quadrant of the tympanic membrane. A few reports have described bilateral CMEC; however, no study has reported symmetrical CMEC as observed in this case. Bilateral tympanoplasty concomitant with cholesteatoma removal was performed, and histopathological evaluation of the resected specimen showed closed-type cholesteatoma. In this report, we describe a rare case of symmetric CMEC, which supports the epidermoid formation theory associated with CMEC, together with a literature review.
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OBJECTIVE: To investigate the impairment patterns in peripheral vestibular organs in sudden sensorineural hearing loss (SSNHL) with and without vertigo. STUDY DESIGN: Retrospective study. SETTING: Single tertiary medical center. METHODS: Data from 165 SSNHL patients in a tertiary referral center from January 2017 to December 2022 were retrospectively analyzed. All patients underwent a video head impulse test, vestibular evoked myogenic potential test, and pure-tone audiometry. Hierarchical cluster analysis was performed to investigate vestibular impairment patterns. The prognosis of the hearing was determined using American Academy of Otolaryngology-Head and Neck Surgery recommendations. RESULTS: After excluding patients with vestibular schwannoma and Meniere's disease, 152 patients were included in this study. A total of 73 of 152 patients were categorized as SSNHL with vertigo (SSNHL_V) and showed an independent merge of the posterior semicircular canal (PSCC) in cluster analysis. A total of 79 of 152 patients were categorized as SSNHL without vertigo (SSNHL_N) and showed an independent merge of saccule in cluster analysis. The PSCC (56.2%) and saccule (20.3%) were the most frequently impaired vestibular organs in SSNHL_V and SSNHL_N, respectively. In terms of prognosis, 106 of 152 patients had partial/no recovery and showed an independent merge of the PSCC in cluster analysis. A total of 46 of 152 patients had a complete recovery and showed an independent merge of the saccule in cluster analysis. CONCLUSION: A tendency of isolated PSCC dysfunction was seen in SSNHL_V and partial/no recovery. A tendency of isolated saccular dysfunction was seen in SSNHL_N and complete recovery. Different treatments might be needed in SSNHL depending on the presence of vertigo.
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Perda Auditiva Neurossensorial , Perda Auditiva Súbita , Vestíbulo do Labirinto , Humanos , Estudos Retrospectivos , Vertigem/etiologia , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Súbita/diagnóstico , Perda Auditiva Súbita/etiologia , Audiometria de Tons PurosRESUMO
The signaling pathways governing acetaminophen (APAP)-induced liver injury have been extensively studied. However, little is known about the ubiquitin-modifying enzymes needed for the regulation of APAP-induced liver injury. Here, we examined whether the Pellino3 protein, which has E3 ligase activity, is needed for APAP-induced liver injury and subsequently explored its molecular mechanism. Whole-body Peli3-/- knockout (KO) and adenovirus-mediated Peli3 knockdown (KD) mice showed reduced levels of centrilobular cell death, infiltration of immune cells, and biomarkers of liver injury, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), upon APAP treatment compared to wild-type (WT) mice. Peli3 deficiency in primary hepatocytes decreased mitochondrial and lysosomal damage and reduced the mitochondrial reactive oxygen species (ROS) levels. In addition, the levels of phosphorylation at serine 9 in the cytoplasm and mitochondrial translocation of GSK3ß were decreased in primary hepatocytes obtained from Peli3-/- KO mice, and these reductions were accompanied by decreases in JNK phosphorylation and mitochondrial translocation. Pellino3 bound more strongly to GSK3ß compared with JNK1 and JNK2 and induced the lysine 63 (K63)-mediated polyubiquitination of GSK3ß. In rescue experiments, the ectopic expression of wild-type Pellino3 in Peli3-/- KO hepatocytes restored the mitochondrial translocation of GSK3ß, but this restoration was not obtained with expression of a catalytically inactive mutant of Pellino3. These findings are the first to suggest a mechanistic link between Pellino3 and APAP-induced liver injury through the modulation of GSK3ß polyubiquitination.
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Acetaminofen , Doença Hepática Crônica Induzida por Substâncias e Drogas , Animais , Camundongos , Acetaminofen/efeitos adversos , Fosforilação , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Fígado/metabolismo , Hepatócitos/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVES: The aim of this study was to determine the most effective treatment approach by comparing the impacts of various otolith reduction techniques in patients with apogeotropic lateral semicircular canal benign paroxysmal positional vertigo (LC-BPPV). METHODS: We performed a multicenter randomized prospective study from January to December 2015, involving 72 consecutive patients with apogeotropic LC-BPPV. The patients were divided into three treatment groups: therapeutic head-shaking (group A), the Gufoni-Appiani maneuver (group B), and the cupulolith repositioning maneuver (CuRM; group C). Each group underwent evaluation and treatment up to the fourth week. Treatment success was defined as the disappearance of positional vertigo and nystagmus. RESULTS: This study included 72 patients (49 male and 23 female), with a mean (±standard deviation) age of 55.4±13.5 years. The mean duration of vertigo experienced prior to treatment was 3.9±4.4 days. The mean latency and duration of nystagmus were 2.7±3.0 seconds and 47.9±15.8 seconds, respectively. The overall treatment frequency was 2.0±0.9. The number of treatments differed significantly among the three groups (P<0.05). After 4 weeks, the success rates for groups A, B, and C were 90.5%, 92.3%, and 100%, respectively. No significant difference was observed in the success rate across treatment. METHODS: and periods (P>0.05). However, CuRM was the only method with a 100% treatment success rate. CONCLUSION: While no clear difference was observed among the three treatments for LC-BPPV, CuRM was found to be superior to the other approaches in the long term.
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In reinforcement learning, reward-driven feature learning directly from high-dimensional images faces two challenges: sample-efficiency for solving control tasks and generalization to unseen observations. In prior works, these issues have been addressed through learning representation from pixel inputs. However, their representation faced the limitations of being vulnerable to the high diversity inherent in environments or not taking the characteristics for solving control tasks. To attenuate these phenomena, we propose the novel contrastive representation method, Action-Driven Auxiliary Task (ADAT), which forces a representation to concentrate on essential features for deciding actions and ignore control-irrelevant details. In the augmented state-action dictionary of ADAT, the agent learns representation to maximize agreement between observations sharing the same actions. The proposed method significantly outperforms model-free and model-based algorithms in the Atari and OpenAI ProcGen, widely used benchmarks for sample-efficiency and generalization.
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Algoritmos , Reforço Psicológico , Aprendizagem , RecompensaRESUMO
Plastic pollution has been a significant and widespread global issue, and the recent COVID-19 pandemic has been attributed to its worsening effect as plastics have been contaminated with the deadly infectious virus. Microplastics (MPs) may have played a role as a vector that carries hazardous microbes such as emerging bacterial threats (i.e. antibiotic resistant bacteria) and deadly viruses (e.g., coronavirus); this causes great concern over microplastics contaminated with emerging contaminants. Mitigation and treatment of MPs are challenging because of a range of factors including but not limited to physicochemical properties and composition of MPs and pH and salinity of the solution. Despite the heterogeneous nature of aquatic systems, research has overlooked interactions between contaminants and MPs under environmental conditions, degradation pathways of MPs with adsorbed contaminants, and, especially, the role of adsorbed contaminants in the efficiency of MP treatment through membrane filtration, in comparison with other treatment methods. This review aims to (1) analyze an assortment of factors that could influence the removal of MPs and mechanisms of contaminant adsorption on MPs, (2) identify mechanisms influencing membrane filtration of MPs, (3) examine the fate and transport of MPs with adsorbed contaminants, (4) evaluate membrane filtration of contaminant-adsorbing MPs in comparison to other treatment methods, and (5) draw conclusions and the future outlook based on a literature analysis.
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Osteoporosis is characterized by a decrease in bone microarchitecture with an increased risk of fracture. Long-term use of primary treatments, such as bisphosphonates and selective estrogen receptor modulators, results in various side effects. Therefore, it is necessary to develop alternative therapeutics derived from natural products. Crataegus pinnatifida Bunge (CPB) is a dried fruit used to treat diet-induced indigestion, loss of appetite, and diarrhea. However, research into the effects of CPB on osteoclast differentiation and osteoporosis is still limited. In vitro experiments were conducted to examine the effects of CPB on RANKL-induced osteoclast differentiation in RAW 264.7 cells. Moreover, we investigated the effects of CPB on bone loss in the femoral head in an ovariectomized rat model using microcomputed tomography. In vitro, tartrate-resistant acid phosphatase (TRAP) staining results showed the number of TRAP-positive cells, and TRAP activity significantly decreased following CPB treatment. CPB also significantly decreased pit formation. Furthermore, CPB inhibited osteoclast differentiation by suppressing NFATc1, and c-Fos expression. Moreover, CPB treatment inhibited osteoclast-related genes, such as Nfatc1, Ca2, Acp5, mmp9, CtsK, Oscar, and Atp6v0d2. In vivo, bone mineral density and structure model index were improved by administration of CPB. In conclusion, CPB prevented osteoclast differentiation in vitro and prevented bone loss in vivo. Therefore, CPB could be a potential alternative medicine for bone diseases, such as osteoporosis.
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Background: Intratympanic gentamicin injection (ITG) is a well-accepted means to treat intractable Meniere's disease (MD).Aims/Objectives: To investigate change of vestibule-ocular reflex (VOR) gain and pure-tone threshold after low-dose ITG for MD.Methods: Sixteen patients with definite MD who were treated by low-dose ITG were retrospectively reviewed. We defined VOR gain difference as an amount of decreased gain in video head impulse test one month after ITG. Patients were classified into two groups: single injection vs. multiple injections. Multiple injections group was composed of patients with poor vertigo control after initial ITG who required second or third ITG later in follow up period.Results: VOR gain differences of both horizontal and posterior canal plane were higher than those of anterior canal plane. Between two groups, mean VOR gain difference of horizontal canal plane in multiple injections group was lower than that in single injection group. Only two patients showed increased pure-tone threshold more than 10 dB.Conclusion and significance: Our results suggest that ITG appears to cause a differential loss of function across three semicircular canals. Furthermore, if VOR gain difference of horizontal canal is relatively low after initial ITG, patient might have poor vertigo control and be required another ITG.