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Lung-resident memory B cells (MBCs) provide localized protection against reinfection in respiratory airways. Currently, the biology of these cells remains largely unexplored. Here, we combined influenza and SARS-CoV-2 infection with fluorescent-reporter mice to identify MBCs regardless of antigen specificity. We found that two main transcriptionally distinct subsets of MBCs colonized the lung peribronchial niche after infection. These subsets arose from different progenitors and were both class switched, somatically mutated, and intrinsically biased in their differentiation fate toward plasma cells. Combined analysis of antigen specificity and B cell receptor repertoire segregated these subsets into "bona fide" virus-specific MBCs and "bystander" MBCs with no apparent specificity for eliciting viruses generated through an alternative permissive process. Thus, diverse transcriptional programs in MBCs are not linked to specific effector fates but rather to divergent strategies of the immune system to simultaneously provide rapid protection from reinfection while diversifying the initial B cell repertoire.
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COVID-19 , Memória Imunológica , Animais , Linfócitos B , Pulmão , Células B de Memória , Camundongos , Reinfecção , SARS-CoV-2RESUMO
PURPOSE: This overview of reviews aimed to summarize the prevalence of burnout and the dimensions of burnout (emotional exhaustion, depersonalization, and personal accomplishment) in oncology professionals around the world. METHODS: The CINAHL, Embase, PsycINFO, and PubMed databases were searched from inception to September 13, 2023. AMSTAR 2 was used to assess the quality of reviews. The overlap between reviews was calculated. RESULTS: Twelve reviews were included. Overall, reviews showed that burnout was prevalent in oncologists and oncology nurses. On the other hand, no reviews meta-analyzed the prevalence of burnout in oncology radiation therapists. In addition, the dimensions of burnout, high emotional exhaustion, high depersonalization, and low personal accomplishment were highly prevalent across reviews in oncologists, oncology nurses, and oncology radiation therapists. In oncologists, the Americas (specifically Canada) showed the highest prevalence rates for high emotional exhaustion, whereas high depersonalization and low personal accomplishment were mainly prevalent in Europe and Asia, respectively. In oncology nurses, high emotional exhaustion and high depersonalization were mainly prevalent in Asia, whereas low personal accomplishment was more prevalent in the Americas (specifically Canada). The prevalence of overall levels of burnout was not meta-analyzed by continents. CONCLUSION: Some methodological improvements may help to make more robust the findings of this overview (e.g., specific subgroup meta-analyses by oncology specialties), which may help readers reach more precise, direct, and consistent findings. PROTOCOL REGISTRATION: https://doi.org/10.17605/OSF.IO/QPWG5 .
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Esgotamento Psicológico , Radioterapia (Especialidade) , Humanos , Prevalência , Revisões Sistemáticas como Assunto , Oncologia , Exaustão EmocionalRESUMO
PURPOSE: To summarize the available evidence from systematic reviews with meta-analysis on the effects of music-based interventions in adults diagnosed with cancer. METHODS: An overview of systematic reviews was conducted. CINHAL, Embase, PEDro, PubMed, Scopus, the Cochrane Library and Web of Science were searched from inception until November 2022. Systematic reviews with meta-analysis in individuals with cancer (any type), any comparator, and outcomes of cancer-related pain, fatigue, and psychosocial symptoms were eligible. The methodological quality of systematic reviews and the amount of spin of information in the abstract were assessed. The Graphical Representation of Overlap for OVErviews tool (GROOVE) was used to explore the overlap of primary studies among systematic reviews. RESULTS: Thirteen systematic reviews, with over 9000 participants, containing 119 randomized trials and 34 meta-analyses of interest, were included. Music-based interventions involved passive music listening or patients' active engagement. Most systematic reviews lacked a comprehensive search strategy, did not assess the certainty in the evidence and discussed their findings without considering the risk of bias of primary studies. The degree of overlap was moderate (5.81%). Overall, combining music-based interventions and standard care seems to be more effective than standard care to reduce cancer-related pain, fatigue, and distress. Mixed findings were found for other psychosocial measures. CONCLUSION: Music-based interventions could be an interesting approach to modulate cancer-related pain, fatigue, and distress in adults with cancer. The variability among interventions, together with important methodological biases, detract from the clinical relevance of these findings.
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Dor do Câncer , Música , Neoplasias , Adulto , Humanos , Música/psicologia , Ansiedade , Dor do Câncer/etiologia , Dor do Câncer/terapia , Revisões Sistemáticas como Assunto , Neoplasias/complicações , Neoplasias/terapia , Neoplasias/psicologia , Fadiga/etiologia , Fadiga/terapiaRESUMO
OBJECTIVE: To summarise the effect of mind-body exercises on anxiety and depression symptoms in adults with anxiety or depressive disorders. DESIGN: Systematic review with meta-analysis and meta-regression. DATA SOURCES: Five electronic databases were searched from inception to July 2022. Manual searches were conducted to explore clinical trial protocols, secondary analyses of clinical trials and related systematic reviews. ELIGIBILITY CRITERIA: Randomised clinical trials evaluating qigong, tai chi or yoga styles with anxiety or depression symptoms as the outcomes were included. No intervention, waitlist or active controls were considered as control groups. The risk of bias and the certainty of the evidence were assessed. Meta-analyses, meta-regressions and sensitivity analyses were performed. RESULTS: 23 studies, comprising 22 different samples (n=1420), were included. Overall, meta-analyses showed yoga interventions were superior to controls in reducing anxiety symptoms in anxiety disorders. Furthermore, yoga-based interventions decreased depression symptoms in depressive disorders after conducting sensitivity analyses. No differences between groups were found in the rest of the comparisons. However, the certainty of the evidence was judged as very low for all outcomes due to concerns of high risk of bias, indirectness of the evidence, inconsistency and imprecision of the results. In addition, there was marked heterogeneity among yoga-based interventions and self-reported tools used to evaluate the outcomes of interest. CONCLUSION: Although yoga-based interventions may help to improve mental health in adults diagnosed with anxiety or depressive disorders, methodological improvements are needed to advance the quality of clinical trials in this field. PROSPERO REGISTRATION NUMBER: CRD42022347673.
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Transtorno Depressivo , Yoga , Adulto , Humanos , Depressão/terapia , Qualidade de Vida , Ansiedade/terapia , Transtornos de Ansiedade/terapia , Transtorno Depressivo/terapiaRESUMO
Virtual reality is an effective system to train balance and gait in Parkinson's disease, but attrition of this intervention needs to be further examined. This study aims to review and meta-analyze the dropouts of participants in randomized clinical trials that used virtual reality for balance and gait training in people with Parkinson's disease. An electronic search was conducted in PubMed, Web of Science, Scopus and CINAHL. The PEDro scale and Revised Cochrane risk-of-bias tool for randomized trials 2.0 were employed to assess methodological quality. Proportions meta-analysis calculated dropout rate. Odds ratio meta-analysis under 1 indicated lower attrition in experimental participants. Meta-regression identified possible dropouts' moderators. A total of 18 studies were included. The pooled dropout rates were 5.6% (95% CI, 3.3%-9.3%) for all groups, 5.33% (95% CI, 3.03%-9.21%) in virtual reality, and 6.60% (95% CI, 3.84%-26.31%) in comparators. No statistical differences were found in the dropout occurred between the groups (OR 0.83; 95% CI, 0.62-1.12). Number of weeks was the unique moderator (coefficient 0.129, 95% CI 0.018- 0.239; p=0.02). Our overall pooled dropout should be considered in the sample size calculation of future studies. Adequate follow-up of the CONSORT guidelines in the loss report and their reasons could help design suitable retention strategies.
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Doença de Parkinson , Realidade Virtual , Humanos , Equilíbrio Postural , Ensaios Clínicos Controlados Aleatórios como Assunto , MarchaRESUMO
PURPOSE: Mind-body practices such as qigong, tai chi, or yoga combine physical movements, deep breathing, and meditation techniques aiming to improve how people self-care. Our purpose was to develop an overview of systematic reviews to summarize the available evidence on the effectiveness of mind-body practices for cancer-related symptoms management. METHODS: CINAHL, Embase, PsycINFO, PubMed, and the Cochrane Library were used to search systematic reviews with meta-analysis from inception until March 2022. Cancer-related symptoms such as fatigue, pain, psychological measures, and overall quality of life were chosen as outcomes of interest. The methodological quality of each systematic review was assessed using AMSTAR 2. Citation matrices were developed, and the corrected covered area was calculated to explore the potential primary study overlap. RESULTS: A total of 38 systematic reviews comprising 134 distinct primary studies and 129 separate meta-analyses were included. The items of AMSTAR 2 regarding the review protocol, the reasons to choose a specific research design, and the provision of a list of studies that justify their exclusion were scarcely performed. The primary study overlap was moderate for qigong trials and high for both tai chi and yoga trials. Mainly, we found that qigong showed promising effects to reduce fatigue. Tai chi produced positive effects in reducing anxiety. Yoga improved anxiety, depression, distress, stress, and overall quality of life. Finally, the effects of mind-body practices on pain were inconsistent. CONCLUSIONS: Qigong, tai chi, and yoga could be effective approaches to relief cancer-related symptoms in adults with different cancer diagnoses.
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Neoplasias , Qigong , Tai Chi Chuan , Yoga , Adulto , Humanos , Qualidade de Vida , Revisões Sistemáticas como Assunto , Fadiga/etiologia , Fadiga/terapia , Neoplasias/complicações , Neoplasias/terapia , DorRESUMO
OBJECTIVE: To investigate the influence of muscle position (relaxed vs stretched) on muscle mechanical properties and the ability of myotonometry to detect differences between sides, groups, and sites of testing in patients with stroke. We also analyzed the association between myotonometry and clinical measures of spasticity. DESIGN: Cross-sectional study. SETTING: Outpatient rehabilitation units including private and public centers. PARTICIPANTS: Seventy-one participants (20 subacute stroke, 20 chronic stroke, 31 controls) were recruited (N=71). INTERVENTION: Muscle mechanical properties were measured bilaterally with a MyotonPRO at muscle belly and musculotendinous sites during 2 protocols (muscle relaxed or in maximal bearable stretched position). MAIN OUTCOME MEASURES: Muscle tone and stiffness of the biceps brachii and gastrocnemius. Poststroke spasticity was evaluated with the Modified Tardieu Scale (MTS). A mixed-model analysis of variance was used to detect differences in the outcome measures. RESULTS: The analysis of variance showed a significant effect of muscle position on muscle mechanical properties (higher tone and stiffness with the muscle assessed in stretched position). Measurements with the stretched muscle could help discriminate between spastic and nonspastic sides, but only at the biceps brachii. Overall, there was a significant increase in tone and stiffness in the chronic stroke group and in myotendinous sites compared with muscle belly sites (all, P<.05). No correlations were found between myotonometry and the MTS. CONCLUSIONS: Myotonometry assessment of mechanical properties with the muscle stretched improves the ability of myotonometry to discriminate between sides in patients after stroke and between people with and without stroke.
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Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Humanos , Espasticidade Muscular/complicações , Estudos Transversais , Acidente Vascular Cerebral/complicações , Músculo Esquelético/fisiologia , BraçoRESUMO
BACKGROUND: Entrepreneurial intention is considered to be the best predictor of entrepreneurial behaviour. The Theory of Planned Behaviour (TPB) explains the degree of correlation between variables such as entrepreneurial intention, perceived feasibility and perceived desirability. Knowing the entrepreneurial intention of students of Health Sciences will help to guide and promote effective university policies to support entrepreneurship. The authors aimed to analyse the entrepreneurial intention of university students in the field of Health Sciences. METHODS: A cross-sectional study was conducted in the Faculties of Health Sciences of two public universities of Southern Spain. 1518 students of different degrees of Health Sciences (Physiotherapy, Podiatry, Dentistry, Nursing and Occupational Therapy), from first to fourth year. An online structured questionnaire was used, the Entrepreneurial Event Model (EEM) adapted to the Spanish context. This measurement model was completed with 8 items from the Motivated Strategies for Learning Questionnaire-MSLQ. RESULTS: The hypothetical model showed that perceived desirability and perceived feasibility were positive and significant predictors of entrepreneurial intention. Perceived desirability showed an indirect effect on entrepreneurial intention through perceived feasibility. Expectation of success and self-efficacy had no direct effect on entrepreneurial intention. CONCLUSIONS: Perceived desirability and perceived feasibility are related to entrepreneurial intention in Health Sciences students.
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Intenção , Autoeficácia , Estudos Transversais , Humanos , Motivação , EstudantesRESUMO
To assess and meta-analyse the pooled dropout rate from the randomised control trilas that use virtual reality for balance or gait rehabilitation in people with multiple sclerosis. A systematic review of randomised control trials with meta-analysis and meta-regressions was performed. A search was conducted in PubMed, Scopus, Web of Science, the Physiotherapy Evidence Database, the Cochrane Database, CINHAL, LILACS, ScienceDirect, and ProQuest. It was last updated in July 2022. After the selection of studies, a quality appraisal was carried out using the PEDro Scale and the Revised Cochrane risk-of-bias tool for randomised trials. A descriptive analysis of main characteristics and dropout information was performed. An overall proportion meta-analysis calculated the pooled dropout rate. Odds ratio meta-analysis compared the dropout likelihood between interventions. The meta-regression evaluated the influence of moderators related to dropout. Sixteen studies with 656 participants were included. The overall pooled dropout rate was 6.6% and 5.7% for virtual reality and 9.7% in control groups. The odds ratio (0.89, p = 0.46) indicated no differences in the probability of dropouts between the interventions. The number, duration, frequency, and weeks of sessions, intervention, sex, multiple sclerosis phenotype, Expanded Disability Status Scale score, and PEDro score were not moderators (p > 0.05). Adverse events were not reported and could not be analysed as moderators. Dropouts across the virtual reality and control comparators were similar without significant differences. Nonetheless, there is a slight trend that could favour virtual reality. Standardisation in reporting dropouts and adverse events is recommended for future trials. PROSPERO database, registration number ID CRD42021284989. Supplementary Information: The online version contains supplementary material available at 10.1007/s10055-022-00733-4.
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OBJECTIVE: To synthesise the existing evidence about the effect of patient education, either used alone or as adjunctive therapy, on the improvement of quality of life, pain and fatigue in adult breast cancer survivors. DATA SOURCES: We searched PubMed, Web of Science, CINAHL, SCOPUS, Cochrane Plus, PEDro, Dialnet and Clinicaltrials.gov databases. METHODS: We conducted this systematic review in accordance with the PRISMA statement. Only randomised controlled trials with adult breast cancer survivors were included. We assessed the methodological quality of the studies using the PEDro scale and the Cochrane risk-of-bias tool. We synthesised evidence using the GRADE tool. RESULTS: We included 14 studies (PEDro 4-8 points) comprising 1749 adult women who survived breast cancer, of which we included 12 in the quantitative analysis. There were statistically significant short-term benefits for improved global quality-of-life (standardised mean difference [SMD] = 0.43, P = 0.05, 95% CI [0.00, 0.85]; GRADE: low certainty; not important), emotional quality-of-life (SMD = 0.32, P = 0.04, 95% CI [0.02, 0.62]) and fatigue (SMD = 0.24, P = 0.0004, 95% CI [0.11, 0.37]; GRADE: low certainty; not important). However, there were not statistically significant for pain severity (SMD = -0.05, P = 0.67, 95% CI [-0.26, 0.17]; GRADE: low certainty; not important) and fear to recurrence (SMD = -0.05, P = 0.68, 95% CI [-0.31, 0.20]; GRADE: moderate certainty; not important). CONCLUSION: Patient education have a significative effect in short-term global quality-of-life, emotional quality-of-life and fatigue, though all the results were classified as 'not important'.
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Neoplasias da Mama , Sobreviventes de Câncer , Adulto , Ansiedade , Depressão , Fadiga/etiologia , Feminino , Humanos , Dor , Educação de Pacientes como Assunto , Qualidade de VidaRESUMO
Background: FOXP3+ regulatory T cells (Tregs) restrain the destructive potential of the immune system. We have previously reported a pronounced reduction in circulating Tregs in infants with severe respiratory syncytial virus (RSV) disease. Because interleukin-2 (IL-2) is critical for Treg growth, survival, and activity, we here analyzed IL-2 production and function in RSV-infected infants. Methods: Phenotype, proliferation, IL-2 production, and IL-2 signaling in CD4+ T cells were analyzed by flow cytometry. Serum soluble CD25 levels were quantified by ELISA. Results: CD4+ T cells from RSV-infected infants produced lower amounts of IL-2 and showed a reduced proliferative response compared with healthy infants. IL-2 increased CD4+ T-cell proliferation and FOXP3 expression in both healthy and RSV-infected infants. However, although IL-2 induced a similar pattern of STAT5 phosphorylation, the proliferative response of CD4+ T cells and the expression of FOXP3+ remained significantly lower in RSV-infected infants. Interestingly, we found a negative correlation between disease severity and both the production of IL-2 by CD4+ T cells and the ability of exogenous IL-2 to restore the pool of FOXP3+CD4+ T cells. Conclusions: A reduced ability to produce IL-2 and a limited response to this cytokine may affect the function of CD4+ T cells in RSV-infected infants.
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Fatores Imunológicos/metabolismo , Interleucina-2/metabolismo , Infecções por Vírus Respiratório Sincicial/patologia , Linfócitos T Reguladores/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Lactente , Subunidade alfa de Receptor de Interleucina-2/sangue , MasculinoRESUMO
OBJECTIVE: To evaluate the evidence for the use of virtual reality to treat balance and gait impairments in multiple sclerosis rehabilitation. DESIGN: Systematic review and meta-analysis of randomized controlled trials and quasi-randomized clinical trials. METHODS: An electronic search was conducted using the following databases: MEDLINE (PubMed), Physiotherapy Evidence Database (PEDro), Cochrane Database of Systematic Reviews (CDSR) and (CINHAL). A quality assessment was performed using the PEDro scale. The data were pooled and a meta-analysis was completed. This systematic review was conducted in accordance with the (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) PRISMA guideline statement. It was registered in the PROSPERO database (CRD42016049360). RESULTS: A total of 11 studies were included. The data were pooled, allowing meta-analysis of seven outcomes of interest. A total of 466 participants clinically diagnosed with multiple sclerosis were analysed. Results showed that virtual reality balance training is more effective than no intervention for postural control improvement (standard mean difference (SMD) = -0.64; 95% confidence interval (CI) = -1.05, -0.24; P = 0.002). However, significant overall effect was not showed when compared with conventional training (SMD = -0.04; 95% CI = -0.70, 0.62; P = 0.90). Inconclusive results were also observed for gait rehabilitation. CONCLUSION: Virtual reality training could be considered at least as effective as conventional training and more effective than no intervention to treat balance and gait impairments in multiple sclerosis rehabilitation.
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Transtornos Neurológicos da Marcha/reabilitação , Esclerose Múltipla/reabilitação , Modalidades de Fisioterapia , Equilíbrio Postural/fisiologia , Jogos de Vídeo , Realidade Virtual , Transtornos Neurológicos da Marcha/fisiopatologia , Humanos , Esclerose Múltipla/fisiopatologiaRESUMO
UNLABELLED: Elucidating the factors that modulate HIV-specific antibody-dependent cellular cytotoxicity (ADCC) will help in understanding its role in HIV immunity. The aim of this study was to determine whether IgA could modify the magnitude of ADCC in HIV infection, abrogating its protective role. Plasma samples from 20 HIV-positive (HIV(+)) subjects enrolled during primary HIV infection (PHI), 10 chronically infected subjects (chronic), and 7 elite controllers (EC) were used. ADCC was determined by using a fluorometric ADCC assay, before and after removal of plasma IgA. Data were analyzed by using nonparametric statistics. ADCC was documented in 80% of PHI enrollment samples and in 100% of PHI 12-month, chronic, and EC samples; it peaked after acute infection, reached a plateau in chronic infection, and decreased after initiation of antiretroviral treatment (ART). Significant associations between ADCC and disease progression were found only after removal of plasma IgA from 12-month PHI samples: the magnitude of ADCC not only increased after IgA removal but also correlated with CD4(+) T-cell preservation. This work provides evidence that gp120-specific IgA was capable of modifying ADCC responses during natural HIV infection for the first time and adds to similar evidence provided in other settings. Furthermore, it underscores the complexity of the ADCC phenomenon and will help in an understanding of its underlying mechanisms. IMPORTANCE: Although the induction of ADCC-mediating antibodies in HIV-infected subjects has been extensively documented, the association of these antibodies with protection from disease progression is poorly understood. Here, we demonstrate that plasma IgA is a factor capable of modifying the magnitude of IgG-mediated ADCC in HIV infection, mitigating its beneficial effect. These results help in understanding why previous studies failed to demonstrate correlations between ADCC and disease progression, and they also contribute to the notion that an HIV vaccine should stimulate the production of ADCC-mediating IgG antibodies but not IgA.
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Citotoxicidade Celular Dependente de Anticorpos , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/imunologia , Imunoglobulina A/imunologia , Viremia/imunologia , Adulto , Idoso , Fluorometria , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemAssuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Receptores de IgG/metabolismo , Infecções por Vírus Respiratório Sincicial/metabolismo , Regulação para Cima/fisiologia , Feminino , Humanos , Lactente , Masculino , Vírus Sinciciais Respiratórios/patogenicidadeRESUMO
Introduction: Cancer-related chronic pain is an important sequelae that damages the quality of life of breast cancer survivors. Pain neuroscience education and graded exposure to movement are therapeutic tools that have been shown to be effective in the management of chronic pain in other populations. However, there are no previous studies that combine them after breast cancer. Objective: To evaluate the effectiveness of an online physiotherapy focused-person program which combines pain neuroscience education and graded exposure to movement for quality of life improvement in breast cancer survivors. Methodology: This protocol is a randomized controlled trial with a sample size of 40 breast cancer survivors with pain in the last 6 months. Participants will be allocated to the experimental or control group using a fixed size block randomization method. The evaluator and statistician will be blinded to participant allocation. Participants in the experimental group will receive a 12-week intervention based on pain neuroscience education and therapeutic yoga as a graded exposure to movement exercise; participants in the control group will continue with their usual cancer-related symptoms care. Both groups will receive an education booklet. The main outcome will be quality of life, measured by the Functional Assessment of Cancer Therapy - Breast (FACT-B+4); secondary, four outcomes related to pain experience (catastrophising, self-efficacy, kinesiophobia and fear-avoidance behaviors) will be also assessed. All variables will be assessed by two blinded evaluators at four timepoints. A mixed-model analyses of variance ANOVA (2 × 4) will be used to study the effects of the treatment on the dependent variables. All statistical tests will be performed considering a confidence interval of 95%. SPSS program will be used for the data analysis. Discussion: This research is expected to contribute to breast cancer rehabilitation field. The proposed intervention is also expected to improve self-care skills related to chronic pain and to empower women regarding the management of their symptoms and quality of life.Clinical trial registration: https://clinicaltrials.gov/, NCT04965909.
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PURPOSE: To develop a systematic review with meta-analysis to summarize the effectiveness of exercise, regular physical activity, and mind-body exercise on harmful exercise habits, psychological factors, and quality of life in people clinically diagnosed with feeding and eating disorders. MATERIAL AND METHODS: Randomized clinical trials and pilot randomized clinical trials were considered. RESULTS: Twelve studies were included. No studies evaluated athletes. No studies examined regular physical activity as the targeted intervention. Quality of life could not be meta-analyzed. Overall, meta-analyses showed that exercise or mind-body exercise was not more effective than controls in reducing depression symptoms, harmful exercise habits, eating behaviors, or emotional regulation skills. However, important methodological and clinical issues were detected in the included studies. This affected the certainty of evidence of the meta-analyzed outcomes which ranged from low to very low. No studies reported in sufficient detail their interventions to be replicated. CONCLUSIONS: Overall, exercise and mind-body exercise may be ineffective in improving meta-analyzed outcomes. However, the certainty of evidence ranged from low to very low and the body of knowledge in this field needs to be increased to reach robust conclusions.
Exercise and mind-boy exercises were not more effective than controls for eating behaviors in eating disorders.Exercise and mind-boy exercises were not more effective than controls for depression symptoms in eating disorders.Clinicians should be aware no specific exercises can be recommended for treating psychological factors in eating disorders.
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Cerebral amyloid ß (Aß) accumulation is pathogenically associated with sporadic Alzheimer's disease (SAD). BACE-1 is involved in Aß generation while insulin-degrading enzyme (IDE) partakes in Aß proteolytic clearance. Vulnerable regions in AD brains show increased BACE-1 protein levels and enzymatic activity while the opposite occurs with IDE. Another common feature in SAD brains is Notch1 overexpression. Here we demonstrate an increase in mRNA levels of Hey-1, a Notch target gene, and a decrease of IDE transcripts in the hippocampus of SAD brains as compared to controls. Transient transfection of Notch intracellular domain (NICD) in N2aSW cells, mouse neuroblastoma cells (N2a) stably expressing human amyloid precursor protein (APP) Swedish mutation, reduce IDE mRNA levels, promoting extracellular Aß accumulation. Also, NICD, HES-1 and Hey-1 overexpression result in decreased IDE proximal promoter activity. This effect was mediated by 2 functional sites located at -379/-372 and -310-303 from the first translation start site in the -575/-19 (556 bp) fragment of IDE proximal promoter. By site-directed mutagenesis of the IDE promoter region we reverted the inhibitory effect mediated by NICD transfection suggesting that these sites are indeed responsible for the Notch-mediated inhibition of the IDE gene expression. Intracranial injection of the Notch ligand JAG-1 in Tg2576 mice, expressing the Swedish mutation in human APP, induced overexpression of HES-1 and Hey-1 and reduction of IDE mRNA levels, respectively. Our results support our theory that a Notch-dependent IDE transcriptional modulation may impact on Aß metabolism providing a functional link between Notch signaling and the amyloidogenic pathway in SAD.
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Precursor de Proteína beta-Amiloide/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Homeodomínio/metabolismo , Insulisina/metabolismo , Regiões Promotoras Genéticas , Transdução de Sinais/fisiologia , Transcrição Gênica , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular , Hipocampo/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Insulisina/genética , Camundongos , Ligação Proteica , Receptores Notch/genética , Receptores Notch/metabolismo , Fatores de Transcrição HES-1RESUMO
BACKGROUND: Musculoskeletal disorders are major causes of morbidity in the world, and these conditions have a strong negative influence in terms of health-related quality of life. The purpose of this study was to evaluate the effect of an 8-week multimodal physical therapy program on general health state and health-related quality of life in patients with chronic musculoskeletal disorders. METHODS: There were 244 participants in this prospective cohort analysis with 8-week follow-up. The primary outcome was general health state (physical and mental components), determined with the Short Form-12 Health Survey (SF-12). The secondary outcome was health related quality of life, determined with the EuroQoL-5D and VAS. The intervention was evaluated by comparing pre- and post-outcome measurements. T-tests were performed for paired data. RESULTS: Differences were statistically significant for physical health state: +1.68 (p < 0.05) (baseline: 42.38); mental health state: +3.15 (p < 0.001) (baseline: 46.57); and health related quality of life: +0.18 (EuroQoL 5D) (baseline: 46.57) and +7.22 (EuroQoL_VAS) (p < 0.001) (baseline: 60.81). Intervention resulted in clinically relevant changes in terms of percentage improvement from baseline scores. CONCLUSIONS: Eight weeks of a Multimodal Physical Therapy Program seemed to moderately enhance the general health state and HRQoL of patients with chronic musculoskeletal diseases. This kind of therapeutic exercise can be recommended to patients with chronic low back pain, chronic neck pain and osteoarthritis, at least in the short term.
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Doenças Musculoesqueléticas/terapia , Modalidades de Fisioterapia/psicologia , Qualidade de Vida/psicologia , Doença Crônica/psicologia , Doença Crônica/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/psicologia , Estudos Prospectivos , Inquéritos e Questionários , Resultado do TratamentoRESUMO
OBJECTIVES: Reference ranges of blood plasma amino acids are required for the diagnosis and management of inherited metabolic disorders affecting one or more amino acids and can significantly impact the clinical decision-making and the quality of patient care. Our objective was to establish the reference values for plasma amino acids in a Spanish population measured by gas chromatography-mass spectrometry (GC-MS). METHODS: Amino acids were extracted, derivatized to N(O)-tert-butyldimethylsilyl, and analyzed by GC-MS. RESULTS: Significant differences in the concentrations of several amino acids have been determined between age groups. Such differences might be due to a combination of several factors, including age, genetic factors, nutritional status, and dietary habits. CONCLUSIONS: The amino acid values are not evidently affected by sex, but they do vary with age. Such data help to provide a basis for diagnosing metabolic abnormalities. To our knowledge, this is the first published article showing the age-related reference ranges for plasma amino acids analyzed by GC-MS.