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Herein, we report a pair of regioselective N 1- and N 2 -alkylations of a versatile indazole, methyl 5-bromo-1H-indazole-3-carboxylate (6) and the use of density functional theory (DFT) to evaluate their mechanisms. Over thirty N 1- and N 2-alkylated products were isolated in over 90% yield regardless of the conditions. DFT calculations suggest a chelation mechanism produces the N 1-substituted products when cesium is present and other non-covalent interactions (NCIs) drive the N 2-product formation. Methyl 1H-indazole-7-carboxylate (18) and 1H-indazole-3-carbonitrile (21) were also subjected to the reaction conditions and their mechanisms were evaluated. The N 1- and N 2-partial charges and Fukui indices were calculated for compounds 6, 18, and 21 via natural bond orbital (NBO) analyses which further support the suggested reaction pathways.
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OBJECTIVE: The aim of this study was to explore the longitudinal associations between baseline quadriceps strength and knee joint structural abnormalities in knee osteoarthritis (KOA). METHODS: This study is a longitudinally observational study based on Osteoarthritis Initiative (OAI) cohort, including men and women aged 45-79. Quadriceps strength was measured by isometric knee extension testing at baseline. Knee joint structural abnormalities, including cartilage damage, bone marrow lesions (BMLs), effusion-synovitis and Hoffa-synovitis, were evaluated by Magnetic Resonance Imaging Osteoarthritis Knee Score (MOAKS) at baseline and 1-year follow-up. Generalized estimating equations were employed to examine the associations between quadriceps strength and knee structural abnormalities. All analyses were stratified by sex. RESULTS: One thousand three hundred thirty-eight participants (523 men and 815 women) with a mean age of 61.8 years and a mean BMI of 29.4 kg/m2 were included in this study. For men, no significantly longitudinal association of quadriceps strength with structural abnormalities was detected. In contrast, quadriceps strength was significantly and negatively associated with changes in cartilage damage and BMLs in lateral patellofemoral joint (PFJ) (cartilage damage: OR: 0.91, 95% CI 0.84 to 0.99, P = 0.023; BMLs: OR: 0.85, 95% CI 0.74 to 0.96, P = 0.011) and effusion-synovitis (OR = 0.88, 95% CI 0.78 to 0.99, P = 0.045) among females longitudinally. Higher quadriceps strength was significantly associated with less progression of lateral PFJ cartilage damage, BMLs and effusion-synovitis in females. CONCLUSIONS: Higher quadriceps strength was associated with changes in cartilage damage and BMLs within the lateral PFJ and effusion-synovitis among females, suggesting the potential protective role of quadriceps strength on joint structures in women.
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Doenças das Cartilagens , Cartilagem Articular , Osteoartrite do Joelho , Sinovite , Doenças das Cartilagens/patologia , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologia , Feminino , Humanos , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/patologia , Índice de Gravidade de Doença , Sinovite/patologiaRESUMO
The identification of damage based on Lamb waves can hardly avoid obtaining the reference signal under healthy conditions. A non-reference damage localization (NRDL) method is proposed in this paper. The NRDL method is established by the improved two-arrival-time difference method (2/ATDM) and BFGS method. The layout principles of the piezoelectric ceramic lead zirconate titanate (PZT) transducer array in the specimen are proposed. In contrast to existing methods, the damage outside the array in the specimen is identified based on the NRDL. The full-area damage location in the specimen is realized. Furthermore, the optimization of the excitation signal center frequency and transducer array layout is carried out. The damage location accuracy is greatly improved.
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Cerâmica , TransdutoresRESUMO
Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies.
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Cromossomos Humanos Par 3/genética , Neoplasias Pulmonares/genética , Proteínas de Ligação a RNA/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Variações do Número de Cópias de DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Prognóstico , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Análise de Sobrevida , Resultado do TratamentoRESUMO
Acute viral infections typically generate functional effector CD8(+) T cells (TCD8) that aid in pathogen clearance. However, during acute viral lower respiratory infection, lung TCD8 are functionally impaired and do not optimally control viral replication. T cells also become unresponsive to Ag during chronic infections and cancer via signaling by inhibitory receptors such as programmed cell death-1 (PD-1). PD-1 also contributes to TCD8 impairment during viral lower respiratory infection, but how it regulates TCD8 impairment and the connection between this state and T cell exhaustion during chronic infections are unknown. In this study, we show that PD-1 operates in a cell-intrinsic manner to impair lung TCD8. In light of this, we compared global gene expression profiles of impaired epitope-specific lung TCD8 to functional spleen TCD8 in the same human metapneumovirus-infected mice. These two populations differentially regulate hundreds of genes, including the upregulation of numerous inhibitory receptors by lung TCD8. We then compared the gene expression of TCD8 during human metapneumovirus infection to those in acute or chronic lymphocytic choriomeningitis virus infection. We find that the immunophenotype of lung TCD8 more closely resembles T cell exhaustion late into chronic infection than do functional effector T cells arising early in acute infection. Finally, we demonstrate that trafficking to the infected lung alone is insufficient for TCD8 impairment or inhibitory receptor upregulation, but that viral Ag-induced TCR signaling is also required. Our results indicate that viral Ag in infected lungs rapidly induces an exhaustion-like state in lung TCD8 characterized by progressive functional impairment and upregulation of numerous inhibitory receptors.
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Linfócitos T CD8-Positivos/imunologia , Metapneumovirus/imunologia , Infecções por Paramyxoviridae/imunologia , Infecções Respiratórias/imunologia , Doença Aguda , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Análise por Conglomerados , Perfilação da Expressão Gênica/métodos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , Metapneumovirus/fisiologia , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Infecções por Paramyxoviridae/genética , Infecções por Paramyxoviridae/virologia , Fenótipo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Infecções Respiratórias/genética , Infecções Respiratórias/virologia , Baço/imunologia , Baço/metabolismo , Baço/virologia , Transcriptoma/genética , Transcriptoma/imunologiaRESUMO
BACKGROUND: Rhinovirus is linked to asthma exacerbations and chronic obstructive pulmonary disease exacerbations in adults. The severity and rates of rhinovirus acute respiratory illnesses (ARIs) in adults are uncertain. OBJECTIVES: We sought to determine rhinovirus-associated ARI rates in adults presenting for care in multiple settings and identify factors associated with rhinovirus detection. METHODS: This prospective, population-based cohort enrolled Tennessee residents 18 years or older in the emergency department (ED), outpatient clinics, or hospitalized for ARI from December 2008 to May 2010. Nasal/throat swabs were collected and tested for rhinovirus and other viruses by using RT-PCR. Rates of ED visits and hospitalizations were calculated and rhinovirus-positive and rhinovirus-negative patients were compared. RESULTS: Among 2351 enrollees, rhinovirus was detected in 247 (11%). There were 7 rhinovirus-associated ED visits and 3 hospitalizations per 1000 adults annually. Patients with rhinovirus, compared with virus-negative ARI, were more likely to present with wheezing (odds ratio [OR], 1.7; 95% CI, 1.23-2.35; P < .001), to be a current smoker (OR, 2.31; 95% CI, 1.68-3.19) or live with a smoker (OR, 1.72; 95% CI, 1.10-2.67), have a history of chronic respiratory disease (OR, 1.61; 95% CI, 1.17-2.22), and were less likely to be hospitalized versus seen in the outpatient setting (OR, 0.58; 95% CI, 0.41-0.83). CONCLUSIONS: Rhinovirus is associated with a substantial number of ED visits and hospitalizations for ARIs in adults. There may be modifiable factors that can reduce the likelihood of presenting with rhinovirus-associated ARIs.
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Assistência Ambulatorial , Hospitalização , Infecções por Picornaviridae/epidemiologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia , Rhinovirus , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Vigilância em Saúde Pública , Sons Respiratórios , Fatores de Risco , Estações do Ano , Tennessee/epidemiologia , Adulto JovemRESUMO
BACKGROUND & AIMS: Chronic inflammation contributes to the pathogenesis of gastric tumorigenesis. The aurora kinase A (AURKA) gene is frequently amplified and overexpressed in gastrointestinal cancers. We investigated the roles of AURKA in inflammation and gastric tumorigenesis. METHODS: We used quantitative real-time reverse transcription polymerase chain reaction, immunofluorescence, immunohistochemistry, luciferase reporter, immunoblot, co-immunoprecipitation, and in vitro kinase assays to analyze AGS and MKN28 gastric cancer cells. We also analyzed Tff1(-/-) mice, growth of tumor xenografts, and human tissues. RESULTS: We correlated increased expression of AURKA with increased levels of tumor necrosis factor-α and inflammation in the gastric mucosa of Tff1(-/-) mice (r = 0.62; P = .0001). MLN8237, an investigational small-molecule selective inhibitor of AURKA, reduced nuclear staining of nuclear factor-κB (NF-κB) p65 in human gastric cancer samples and mouse epithelial cells, suppressed NF-κB reporter activity, and reduced expression of NF-κB target genes that regulate inflammation and cell survival. Inhibition of AURKA also reduced growth of xenograft tumors from human gastric cancer cells in mice and reversed the development of gastric tumors in Tff1(-/-) mice. AURKA was found to regulate NF-κB activity by binding directly and phosphorylating IκBα in cells. Premalignant and malignant lesions from the gastric mucosa of patients had increased levels of AURKA protein and nuclear NF-κB, compared with healthy gastric tissue. CONCLUSIONS: In analyses of gastric cancer cell lines, human tissue samples, and mouse models, we found AURKA to be up-regulated during chronic inflammation to promote activation of NF-κB and tumorigenesis. AURKA inhibitors might be developed as therapeutic agents for gastric cancer.
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Adenocarcinoma/metabolismo , Aurora Quinase A/metabolismo , Carcinogênese/metabolismo , Inflamação/metabolismo , Neoplasias Gástricas/metabolismo , Regulação para Cima , Adenocarcinoma/patologia , Animais , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase A/efeitos dos fármacos , Azepinas/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Xenoenxertos , Humanos , Técnicas In Vitro , Camundongos Knockout , Camundongos Nus , NF-kappa B/metabolismo , Peptídeos/deficiência , Peptídeos/genética , Peptídeos/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Neoplasias Gástricas/patologia , Fator Trefoil-1RESUMO
Although tumor deposits have been associated with poor prognosis in colorectal carcinoma, the prevalence and clinical significance of tumor deposits in rectal adenocarcinoma following neoadjuvant chemoradiation are relatively unexplored. The aims of this study are to assess the clinical significance of tumor deposits in rectal adenocarcinoma patients, including those receiving neoadjuvant therapy. Pathology slides and medical records from 205 consecutive patients who underwent resection for rectal adenocarcinoma between 1990 and 2010 at a single tertiary care center were reviewed. Patients with tumor deposits had higher tumor grade (P=0.006) and worse tumor stage (P<0.001) at presentation than patients without tumor deposits. Among 110 patients who underwent neoadjuvant chemoradiation, tumor deposits were associated with higher rates of lymph node involvement (P=0.035) and distant metastases (P=0.006), and decreased survival (P=0.027). These patients had a trend toward lower treatment response scores (P=0.285) and higher local recurrence (P=0.092). Of 52 patients with tumor deposits, those who underwent neoadjuvant chemoradiation had significantly worse pretreatment stage by endoscopic ultrasound (P<0.001) but interestingly had significantly lower rates of lymphovascular invasion on resection (P<0.001) compared with those who had not received neoadjuvant chemoradiation. Despite treatment with neoadjuvant chemoradiation, tumor deposits were present in over one-fifth of rectal adenocarcinoma patients. Overall, the outcome of patients with tumor deposits in treated and untreated patients were similar, however the association of tumor deposits with deeply invasive tumors and less tumor regression when comparing with treated patients without tumor deposits raises the possibility that these tumors could have a more aggressive biology, possibly explaining the association of tumor deposits with higher rates of recurrence and lower survival after neoadjuvant chemoradiation. Overall, tumor deposits appear to be a poor prognostic marker among rectal adenocarcinoma patients following neoadjuvant chemoradiation and may identify a subset of patients who require aggressive adjuvant therapy to prevent recurrence.
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Adenocarcinoma/patologia , Neoplasias Retais/patologia , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Idoso , Quimiorradioterapia , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Prognóstico , Neoplasias Retais/mortalidade , Neoplasias Retais/terapia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Chronic inflammation and decreased frequency of regulatory T cells (Tregs) in visceral adipose tissue contribute to the propagation of insulin resistance to diabetes mellitus. We tested the hypothesis that new-onset posttransplantation diabetes mellitus (PTDM) is associated with measurable changes in Treg subsets after allogeneic hematopoietic stem cell transplantation (HSCT). PTDM before day 100 and Treg phenotype at engraftment were determined in 36 HSCT recipients without preceding history of diabetes mellitus. Among patients with new-onset PTDM (N = 24), the frequency of circulating CLA(+) (skin-homing) Tregs was decreased (1.53% vs 3.99%; P = .002) and the percentage of α(4)ß(7)(+) (gut-homing) Tregs was increased (17.9% vs 10.7%; P = .048). In multivariate analysis, patients with PTDM continued to demonstrate elevated ratios of α(4)ß(7)(+) Tregs to CLA(+) Tregs (odds ratio, 18.1; P = .020). PTDM is associated with altered immune regulation after HSCT and could represent a target to modulate alloreactivity.
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Diabetes Mellitus/sangue , Transplante de Células-Tronco Hematopoéticas/métodos , Complicações Pós-Operatórias/sangue , Linfócitos T Reguladores/metabolismo , Adulto , Idoso , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/etiologia , Feminino , Citometria de Fluxo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Valor Preditivo dos Testes , Prognóstico , Linfócitos T Reguladores/citologia , Fatores de Tempo , Transplante Homólogo , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Investigations have shown that pulsed lasers tuned to 6.1 µm in wavelength are capable of ablating ocular and neural tissue with minimal collateral damage. This study investigated whether a miniature B-scan forward-imaging optical coherence tomography (OCT) probe can be combined with the laser to provide real-time visual feedback during laser incisions. STUDY DESIGN/METHODS AND MATERIALS: A miniature 25-gauge B-scan forward-imaging OCT probe was developed and combined with a 250 µm hollow-glass waveguide to permit delivery of 6.1 µm laser energy. A gelatin mixture and both porcine corneal and retinal tissues were simultaneously imaged and lased (6.1 µm, 10 Hz, 0.4-0.7 mJ) through air. The ablation studies were observed and recorded in real time. The crater dimensions were measured using OCT imaging software (Bioptigen, Durham, NC). Histological analysis was performed on the ocular tissues. RESULTS: The combined miniature forward-imaging OCT and mid-infrared laser-delivery probe successfully imaged real-time tissue ablation in gelatin, corneal tissue, and retinal tissue. Application of a constant number of 60 pulses at 0.5 mJ/pulse to the gelatin resulted in a mean crater depth of 123 ± 15 µm. For the corneal tissue, there was a significant correlation between the number of pulses used and depth of the lased hole (Pearson correlation coefficient = 0.82; P = 0.0002). Histological analysis of the cornea and retina tissues showed discrete holes with minimal thermal damage. CONCLUSIONS: A combined miniature OCT and laser-delivery probe can monitor real-time tissue laser ablation. With additional testing and improvements, this novel instrument has the future possibility of effectively guiding surgeries by simultaneously imaging and ablating tissue.
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Córnea/cirurgia , Lasers de Estado Sólido/uso terapêutico , Procedimentos Cirúrgicos Oftalmológicos/instrumentação , Retina/cirurgia , Tomografia de Coerência Óptica/instrumentação , Animais , Córnea/patologia , Procedimentos Cirúrgicos Oftalmológicos/métodos , Retina/patologia , SuínosRESUMO
PURPOSE: It has been suggested that children perceptually adapt to changes in retinal image size in the presence of anisometropia and therefore do not display clinically significant aniseikonia. However, given that early methods of eikonometry were not child-friendly, the prevalence of this condition in children is poorly understood. Retinal image size differences may be relevant in the discussion of amblyogenesis. The computer-based Aniseikonia Inspector Version 3 (AI3) uses a simple, forced-choice method and includes calibration for heterophoria. The present study is designed to evaluate AI3 by measuring background and induced aniseikonia in children aged 5 to 13 years. METHODS: All subjects were present for a standard-of-care eye examination and had at least 20/40 best-corrected visual acuity and no history of strabismus or amblyopia. Trials of AI3 were performed in the vertical direction only, using the 12-point test, and two trials were recorded. Each subject was randomized to have a 4% size lens added to either the right eye or the left eye. Two trials were performed in this manner, followed by two more trials with the size lens over the alternate eye. RESULTS: Eighteen children were enrolled; three subjects were not able to complete testing because of lack of attention or understanding. Results from each condition (background aniseikonia, induced aniseikonia OD, and induced aniseikonia OS) were averaged for each patient. With the 4% size lens over the OD, mean aniseikonia measured -3.83%. With the 4% size lens over the OS, mean aniseikonia measured 4.29%. CONCLUSIONS: Most children were able to complete aniseikonia testing with AI3. Background aniseikonia was clinically insignificant (0.59%), and induced aniseikonia measurements were close to expected values using a 4% size lens. Aniseikonia Inspector Version 3 appears to be a useful means for measuring aniseikonia in a normal pediatric population. Further study in children with anisometropia is needed.
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Aniseiconia/diagnóstico , Diagnóstico por Computador/métodos , Refração Ocular/fisiologia , Adolescente , Aniseiconia/fisiopatologia , Criança , Pré-Escolar , Comportamento de Escolha , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Software , Percepção Espacial/fisiologia , Testes Visuais/instrumentação , Acuidade VisualRESUMO
OBJECTIVE: electromyogram (EMG)-driven musculoskeletal models have been widely used to investigate human movements while existing EMG-driven models commonly neglect regional heterogeneity in anatomy and activation within a skeletal muscle. To consider neuromuscular compartment anatomy and activation, a subject- and compartment-specific EMG-driven model was developed for isometric plantarflexion moment prediction. METHODS: the model was hill-type consisting of gastrocnemius medialis, gastrocnemius lateralis, and soleus around the ankle joint, and each muscle was discretised into four compartments. The moment arms of each compartment were determined using magnetic resonance imaging and the compartment activation was calculated based on high-density surface EMG signals. And the hill-type compartment parameters were tuned in a calibration process. The developed compartment-specific model and a generic EMG-driven model were examined by comparing their predicted net ankle moments with measurements obtained while subjects performed isometric plantarflexion tasks at different contraction levels. RESULTS: compared to the generic EMG-driven model, the isometric plantarflexion moment prediction using the compartment-specific model was more accurate at all contraction levels, with the average prediction error decreasing from average 13.81% to 10.11%. The contraction of each compartment was found to be generally non-uniform at all contraction levels. CONCLUSION: the developed compartment-specific model enabled accurate prediction of isometric plantarflexion moment and the simulation of non-uniform muscular contraction, which is more physiologically appropriate than the existing EMG-driven models. SIGNIFICANCE: the proposed compartment-specific formulation opens new perspectives for subject-specific musculoskeletal modelling, which has great potential in understanding regional characteristics of the neuromuscular activities.
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Articulação do Tornozelo , Eletromiografia , Contração Isométrica , Modelos Biológicos , Músculo Esquelético , Humanos , Eletromiografia/métodos , Músculo Esquelético/fisiologia , Músculo Esquelético/diagnóstico por imagem , Contração Isométrica/fisiologia , Masculino , Articulação do Tornozelo/fisiologia , Articulação do Tornozelo/diagnóstico por imagem , Adulto , Feminino , Adulto Jovem , Imageamento por Ressonância Magnética/métodos , Fenômenos Biomecânicos/fisiologiaRESUMO
The high incidence of adolescent depression has become the focus of social and academic attention. Exercise is an important method to improve adolescent depression, but its intervention effect is still controversial. This study first compares and analyzes the relevant studies at home and abroad and finds that exercise prescription in adolescent depression intervention is not accurate enough. A meta-analysis was conducted to develop a precise exercise intervention strategy for adolescent depression. Firstly, this thesis identified how to optimize five elements (exercise intensity, exercise frequency, exercise time, exercise cycle, and exercise type) of exercise prescription to improve depression in adolescents. This is the problem. Furthermore, the concept of "precision exercise" was proposed, and a precision exercise intervention strategy (moderate-intensity aerobic exercise for 8-10 weeks, 3 times/week, 45-50 min/time) was constructed to improve adolescent depression. This paper also presents research that strengthens the cross-sectional research and empirical research on adolescent depression and establishes a precision exercise prescription database for adolescent depression in China. In conclusion, this study not only puts forward the concept of "precision exercise" but also constructs a precision exercise intervention strategy for adolescent depression, which has important theoretical and practical significance for improving the high incidence of adolescent depression.
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Depressão , Terapia por Exercício , Humanos , Adolescente , Estudos Transversais , Terapia por Exercício/métodos , Exercício Físico , ChinaRESUMO
Background: Renal interstitial fibrosis is the pathophysiological basis of type 2 diabetes mellitus (T2DM). Exercise appears to improve kidney interstitial fibrosis in T2DM, in which silent information regulator factor 2-related enzyme 1 (Sirt1) is a critical regulator. However, the role of Sirt1 in mediating exercise on renal tissue as well as its mechanism remains unknown. Methods: T2DM mouse models were created using a high-fat diet mixed with streptozotocin, followed by 8 weeks of treadmill exercise and niacinamide (Sirt1 inhibitor) intervention. Kits for detecting biochemical indices of renal function were used. The pathological appearance and severity of renal tissue were examined using hematoxylin and eosin, Masson and immunohistochemical staining. The mRNA and protein expression of relevant signaling pathway factors were determined to use real-time reverse transcriptase-polymerase chain reaction and western blotting. Results: T2DM can promote renal interstitial fibrosis, increase kidney index, serum creatinine, blood urea nitrogen and 24 h urinary total protein and cause pathological changes in renal tissue and affect renal function. After 8 weeks of exercise intervention, the biochemical indicators in the kidney of T2DM mice were decreased, Sirt1 expression was increased, the expression of TGF-ß1, Smad3, collagen type I (COL1) and collagen type III (COL3) were decreased, and the renal interstitial fibrosis, renal tissue structural lesions and renal function were improved. However, after the nicotinamide intervention, renal interstitial fibrosis of T2DM mice was aggravated, and the improvement effect of exercise on renal interstitial fibrosis of T2DM mice was abolished. Conclusion: The upregulation of Sirt1 expression by exercise can inhibit the transforming growth factor ß1/Smad3 pathway, thereby inhibiting the expression and deposition of COL1 and COL3 in renal interstitium, thereby improving renal interstitial fibrosis in T2DM.
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Low back pain (LBP) is one of the most prevalent and disabling disease worldwide. However, the specific biomechanical changes due to LBP are still controversial. The purpose of this study was to estimate the lumbar and lower limb kinematics, lumbar moments and loads, muscle forces and activation during walking in healthy adults and LBP. A total of 18 healthy controls and 19 patients with chronic LBP were tested for walking at a comfortable speed. The kinematic and dynamic data of the subjects were collected by 3D motion capture system and force plates respectively, and then the motion simulation was performed by OpenSim. The OpenSim musculoskeletal model was used to calculate lumbar, hip, knee and ankle joint angle variations, lumbar moments and loads, muscle forces and activation of eight major lumbar muscles. In our results, significant lower lumbar axial rotation angle, lumbar flexion/extension and axial rotation moments, as well as the muscle forces of the four muscles and muscle activation of two muscles were found in patients with LBP than those of the healthy controls (p < 0.05). This study may help providing theoretical support for the evaluation and rehabilitation treatment intervention of patients with LBP.
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Postoperative pain (POP) is a major clinical challenge. Local anesthetics (LAs), including amide-type LAs, ester-type LAs, and other potential ion-channel blockers, are emerging as drugs for POP management because of their effectiveness and affordability. However, LAs typically exhibit short durations of action and prolonging the duration by increasing their dosage or concentration may increase the risk of motor block or systemic local anesthetic toxicity. In addition, techniques using LAs, such as intrathecal infusion, require professional operation and are prone to catheter displacement, dislodgement, infection, and nerve damage. With the development of materials science and nanotechnology, various LAs delivery systems have been developed to compensate for these disadvantages. Numerous delivery systems have been designed to continuously release a safe dose in a single administration to ensure minimal systemic toxicity and prolong pain relief. LAs delivery systems can also be designed to control the duration and intensity of analgesia according to changes in the external trigger conditions, achieve on-demand analgesia, and significantly improve pain relief and patient satisfaction. In this review, we summarize POP pathways, animal models and methods for POP testing, and highlight LAs delivery systems for POP management. STATEMENT OF SIGNIFICANCE: Postoperative pain (POP) is a major clinical challenge. Local anesthetics (LAs) are emerging as drugs for POP management because of their effectiveness and affordability. However, they exhibit short durations and toxicity. Various LAs delivery systems have been developed to compensate for these disadvantages. They have been designed to continuously release a safe dose in a single administration to ensure minimal toxicity and prolong pain relief. LAs delivery systems can also be designed to control the duration and intensity of analgesia to achieve on-demand analgesia, and significantly improve pain relief and patient satisfaction. In this paper, we summarize POP pathways, animal models, and methods for POP testing and highlight LAs delivery systems for POP management.
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Anestésicos Locais , Sistemas de Liberação de Medicamentos , Dor Pós-Operatória , Anestésicos Locais/administração & dosagem , Anestésicos Locais/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Humanos , Animais , Manejo da Dor/métodosRESUMO
Air pollution can cause disease and has become a major global environmental problem. It is currently believed that air pollution may be related to the progression of SSNHL. As a rapidly developing city in recent years, Hefei has serious air pollution. In order to explore the correlation between meteorological variables and SSNHL admissions, we conducted this study. This study investigated the short-term associations between SSNHL patients admitted to the hospital and Hefei climatic variables. The daily data on SSNHL-related hospital admissions and meteorological variables containing mean temperature (T-mean; °C), diurnal temperature range (DTR; °C), atmospheric pressure (AP; Hp), and relative humidity (RH; %), from 2014 to 2021 (2558 days), were collected. A time-series analysis integrating distributed lag non-linear models and generalized linear models was used. PubMed, Embase, Cochrane Library, and Web of Science databases were searched. Literature published up to August 2023 was reviewed to explore the potential impact mechanisms of meteorological factors on SSNHL. The mechanisms were determined in detail, focusing on wind speed, air pressure, temperature, humidity, and air pollutants. Using a median of 50.00% as a baseline, the effect of exceedingly low T-mean in the single-day hysteresis effect model began at a lag of 8 days (RR = 1.032, 95% CI: 1.001 ~ 1.064). High DTR affected the admission rate for SSNHL on lag 0 day. The significance of the effect was the greatest on that day (RR = 1.054, 95% CI: 1.007 ~ 1.104) and then gradually decreased. High and exceedingly high RH affected the admission rate SSNHL on lag 0 day, and these effects lasted for 8 and 7 days, respectively. There were significant associations between all grades of AP and SSNHL. This is the first study to assess the effect of meteorological variables on SSNHL-related admissions in China using a time-series approach. Long-term exposures to high DTR, RH values, low T-mean values, and all AP grades enhance the incidence of SSNHL in residents. Limiting exposure to extremes of ambient temperature and humidity may reduce the number of SSNHL-related hospital visits in the region. It is advisable to maintain a suitable living environment temperature and avoid extreme temperature fluctuations and high humidity. During periods of high air pollution, it is recommended to stay indoors and refrain from outdoor exercise.
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Poluição do Ar , Conceitos Meteorológicos , China/epidemiologia , Humanos , Poluentes Atmosféricos , Perda Auditiva Neurossensorial/epidemiologia , Temperatura , Umidade , Perda Auditiva Súbita/epidemiologiaRESUMO
Purpose: This study investigated levels of anxiety and sleep quality and their association with physical activity in junior high school students under quarantine during the COVID-19 pandemic. It also tests the effectiveness of physical activity and psychological nursing interventions in alleviating anxiety 'and improving sleep quality. Methods: In July 2021, 14,000 home-quarantined junior high school students in Yangzhou City (China) were selected by random cluster sampling to complete an online survey. We then selected 95 junior high school students for an 8-week longitudinal experiment exploring whether the two types of intervention made positive contributions to students' anxiety, sleep quality, and physical activity. Results: The cross-sectional study revealed that physical activity was significantly related to anxiety and sleep quality. In the longitudinal study, students who underwent the exercise intervention or the psychological nursing intervention experienced significant improvement in their anxiety levels. The exercise intervention also promoted improved sleep quality. Overall, the exercise intervention was more effective than the psychological nursing intervention in reducing levels of anxiety and sleep disorders. Conclusion: During the epidemic period, junior high school students should be encouraged to spend more time engaging in physical activity, and their sleep quality and anxiety shouldbe focused on.
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The mechanism behind the onset of depression has been the focus of current research in the neuroscience field. Silent information regulator 1 (SIRT1) is a key player in regulating energy metabolism, and it can regulate depression by mediating the inflammatory response (e.g., nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß)), gene expression in the nucleus accumben (NAc) and CA1 region of the hippocampus (e.g., nescient helix-loop-helix2 (NHLH2), monoamine oxidase (MAO-A), and 5-Hydroxyindole-3-acetic acid (5-HIAA)), and neuronal regeneration in the CA3 region of the hippocampus. Exercise is an important means to improve energy metabolism and depression, but it remains to be established how SIRT1 acts during exercise and improves depression. By induction and analysis, SIRT1 can be activated by exercise and then improve the function of the hypothalamic-pituitary-adrenal (HPA) axis by upregulating brain-derived neurotrophic factors (BDNF), inhibit the inflammatory response (suppression of the NF-κB and TNF-α/indoleamine 2,3-dioxygenase (IDO)/5-Hydroxytryptamine (5-HT) pathways), and promote neurogenesis (activation of the insulin-like growth factor1 (IGF-1) and growth-associated protein-43 (GAP-43) pathways, etc.), thereby improving depression. The present review gives a summary and an outlook based on this finding and makes an analysis, which will provide a new rationale and insight for the mechanism by which exercise improves depression.
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OBJECTIVE: To investigate whether risk factors related to pain vary at different stages of knee osteoarthritis (OA). METHODS: Individuals from the Osteoarthritis Initiative with available Kellgren/Lawrence (K/L) grade and numerical rating scale (NRS) data at baseline were included in this study. Pain severity was classified into 3 categories based on NRS scores: no pain, mild pain, and moderate/severe pain. Knee OA severity was stratified into 4 categories according to the K/L system. Pain risk factors were evaluated using generalized ordinal logistic regression analysis, and a heatmap was created to compare differences in standardized regression coefficients between subgroups of patients with different knee OA severities. RESULTS: A total of 4,446 subjects were included in this study: 1,574 individuals without pain (35.4%), 1,138 individuals with mild pain (25.6%), and 1,734 individuals with moderate/severe pain (39.0%). For the entire population and subjects in the premorbid-stage subgroup, knee injury history, diabetes mellitus, depression, use of nonsteroidal anti-inflammatory drugs (NSAIDs), and valgus malaligned knees were associated with more severe pain. Older age and stronger quadriceps muscles were associated with milder pain. As the disease progressed, the number of significant risk factors decreased. Only age and quadriceps muscle force remained significant in end-stage disease. CONCLUSION: Multiple factors are associated with pain in patients with knee OA. As the disease progresses, the number of significant risk factors gradually reduces. These findings suggest that strategies for managing pain related to knee OA should vary depending on radiographic grades.