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In solid tumors, the exhaustion of natural killer (NK) cells and cytotoxic T cells in the immunosuppressive tumor microenvironment poses challenges for effective tumor control. Conventional humanized mouse models of hepatocellular carcinoma patient-derived xenografts (HCC-PDX) encounter limitations in NK cell infiltration, hindering studies on NK cell immunobiology. Here, we introduce an improved humanized mouse model with restored NK cell reconstitution and infiltration in HCC-PDX, coupled with single-cell RNA sequencing (scRNA-seq) to identify potential anti-HCC treatments. A single administration of adeno-associated virus carrying human interleukin-15 reinstated persistent NK cell reconstitution and infiltration in HCC-PDX in humanized mice. scRNA-seq revealed NK cell and T cell subpopulations with heightened PDCD1 and TIGIT levels. Notably, combination therapy with anti-PD-1 and anti-TIGIT antibodies alleviated HCC burden in humanized mice, demonstrating NK cell-dependent efficacy. Bulk-RNA sequencing analysis also revealed significant alterations in the tumor transcriptome that may contribute to further resistance after combination therapy, warranting further investigations. As an emerging strategy, ongoing clinical trials with anti-PD-1 and anti-TIGIT antibodies provide limited data. The improved humanized mouse HCC-PDX model not only sheds light on the pivotal role of NK cells but also serves as a robust platform for evaluating safety and anti-tumor efficacy of combination therapies and other potential regimens, complementing clinical insights.
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BACKGROUND: The EQ-5D-Y is a generic preference-weighted measure for children and adolescents which was developed within Europe. Two versions exist, the EQ-5D-Y-3L (Y-3L) and EQ-5D-Y-5L (Y-5L). This study aimed to cross-culturally adapt the Y-3L and Y-5L for use in Singapore and to assess the content validity, specifically, the relevance and comprehensiveness of the EQ-5D-Y descriptive system (DS) in Asia. METHODS: To culturally adapt the instruments, an expert panel consisting of paediatricians and primary school educators were consulted. Modifications suggested by the expert panel were tested via cognitive debriefing interviews with children aged 8-12 in Singapore. To assess the content validity of the EQ-5D-Y DS, interviews were conducted with both healthy (n = 8) and ill children (n = 6) aged 8-15. In the interviews, children discussed their experience with poor health and commented on the comprehensiveness and relevance of the EQ-5D-Y DS. RESULTS: The cross-cultural adaptation process led to minor modifications to the UK English Y-3L and Y-5L versions, including using phrases familiar to the local children and adding examples to facilitate understanding. The five health dimensions in the EQ-5D-Y DS were spontaneously elicited when children discussed their experience with poor health. All health dimensions related to poor health elicited from the interviews fell into three broad categories: physical health (e.g. Appetite, Mobility, and Sleep), mental well-being (e.g. Annoyed/Frustrated and Scared/Worried), and social relationships (e.g. Family and Friends). The EQ-5D-Y DS was generally found to be relevant and comprehensive, although some health dimensions that may be relevant to the local population (Social relationship and Appetite) were not covered. CONCLUSIONS: The UK English EQ-5D-Y instruments were adapted to produce the Singapore English EQ-5D-Y instrument that were comprehensible to local children as young as 8 years old. The EQ-5D-Y DS was generally relevant and comprehensive to measure poor health of local children. Future studies should ascertain the benefits of adding bolt-on items related to social relationships and appetite to the EQ-5D-Y DS.
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Comparação Transcultural , Pesquisa Qualitativa , Qualidade de Vida , Humanos , Singapura , Criança , Masculino , Feminino , Qualidade de Vida/psicologia , Adolescente , Inquéritos e Questionários , Psicometria , Reprodutibilidade dos Testes , Entrevistas como Assunto , Nível de SaúdeRESUMO
Cancer cachexia is a multifactorial syndrome characterized by a significant loss of skeletal muscle, which negatively affects the quality of life. Inhibition of myostatin (Mstn), a negative regulator of skeletal muscle growth and differentiation, has been proven to preserve muscle mass in muscle atrophy diseases, including cachexia. However, myostatin inhibitors have repeatedly failed clinical trials because of modest therapeutic effects and side effects due to the poor efficiency and toxicity of existing delivery methods. Here, we describe a novel method for delivering Mstn siRNA to skeletal muscles using red blood cell-derived extracellular vesicles (RBCEVs) in a cancer cachectic mouse model. Our data show that RBCEVs are taken up by myofibers via intramuscular administration. Repeated intramuscular administrations with RBCEVs allowed the delivery of siRNAs, thereby inhibiting Mstn, increasing muscle growth, and preventing cachexia in cancer-bearing mice. We observed the same therapeutic effects when delivering siRNAs against malonyl-CoA decarboxylase, an enzyme driving dysfunctional fatty acid metabolism in skeletal muscles during cancer cachexia. We demonstrate that intramuscular siRNA delivery by RBCEVs is safe and non-inflammatory. Hence, this method is useful to reduce the therapeutic dose of siRNAs, to avoid toxicity and off-target effects caused by systemic administration of naked siRNAs at high doses.
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Miostatina , Neoplasias , Camundongos , Animais , Miostatina/metabolismo , RNA Interferente Pequeno/metabolismo , Caquexia/etiologia , Caquexia/terapia , Caquexia/metabolismo , Qualidade de Vida , Músculo Esquelético/metabolismo , Neoplasias/complicações , Neoplasias/terapia , Neoplasias/metabolismo , Atrofia Muscular , RNA de Cadeia DuplaRESUMO
The purpose of this study was to investigate the effects of acute nitrate (NO3-)-rich beetroot juice ingestion on explosive and high-intensity exercise performance, oral microbiota composition, and cognitive flexibility (i.e., function), before and after maximal intermittent running exercise. Fifteen women team-sport athletes were assigned in a randomized, double-blind, crossover design to consume concentrated NO3--depleted beetroot juice (PL; 0.1 mmol NO3-) and NO3--rich beetroot juice (BR; 12.0 mmol NO3-) 2.5 h prior to performing a battery of exercise performance tasks and cognitive testing before and after the Yo-Yo intermittent recovery level 1 (YYIR1) running test. Resting plasma [NO3-] and plasma nitrite ([NO2-]) were elevated following BR (P < 0.001). BR did not impact global composition or relative abundance of taxa in the oral microbiome (P > 0.05) or cognitive flexibility before or after exercise (P > 0.05). There was no significant difference in performance during 20-m (PRE, PL: 4.38 ± 0.27 vs. BR: 4.38 ± 0.32 s; POST, PL: 4.45 ± 0.29 vs. BR: 4.43 ± 0.35 s) and 10-m sprints (PRE, PL 2.78 ± 0.15 vs. BR 2.79 ± 0.18 s; POST, PL: 2.82 ± 0.16 vs. BR: 2.81 ± 0.19 s), isokinetic handgrip dynamometry, medicine ball throw, horizontal countermovement jump, or YYIR1 (PL: 355 ± 163 m vs. BR: 368 ± 184 m) between BR and PL (P > 0.05). These findings indicate that acute dietary NO3- may not influence the oral microbiome, explosive and high-intensity exercise performance, or cognitive function in women team-sport athletes.
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PURPOSE: Although the trajectory of mental disorders can be improved with timely treatment, many people defer treatment-seeking. This study aimed to examine the prevalence and correlates of treatment delays for mental disorders in Singapore, as well as perceived effectiveness of treatment received. METHODS: A total of 6126 respondents, aged 18 and above, participated in the Singapore Mental Health Study 2016-a cross-sectional, nationwide study conducted in Singapore from 2016 to 2018. Lifetime treatment contact for mood, anxiety, and alcohol use disorders (AUD) was assessed using the World Mental Health-Composite International Diagnostic Interview (Version 3.0). Multivariable logistic regression was conducted to examine correlates of delayed treatment. RESULTS: A total of 137 participants had made lifetime treatment contact for a mental disorder. The proportion of respondents who received delayed treatment (i.e., at least one year after onset of disorder) was 60.8% for any disorder, 59.5% for mood disorders, 56.3% for anxiety disorders, and 92.7% for AUD. The median delay was 5 years for mood disorders, one year for anxiety disorders, and 4 years for AUD. Treatment delay was significantly associated with older age, higher educational qualification, lifetime AUD, and earlier age of onset of disorder. 58.4% of respondents with lifetime treatment contact had received treatment that they considered effective. CONCLUSION: The high prevalence and long durations of treatment delay underscore the need to encourage help-seeking for mental disorders, especially since treatment is generally perceived to be helpful. Our findings also highlight several population groups more susceptible to receiving delayed treatment.
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Alcoolismo , Transtornos Mentais , Humanos , Saúde Mental , Singapura/epidemiologia , Estudos Transversais , Atraso no Tratamento , Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologia , Transtornos Mentais/terapia , PrevalênciaRESUMO
AIMS: Although the orally available brain-penetrant copper compound CuATSM has demonstrated promising effects in SOD1-linked mouse models, the impact of CuATSM on disease pathology in patients with amyotrophic lateral sclerosis (ALS) remains unknown. METHODS: The present study set out to address this deficit by performing the first pilot comparative analysis of ALS pathology in patients that had been administered CuATSM and riluzole [N = 6 cases composed of ALS-TDP (n = 5) and ALS-SOD1 (n = 1)] versus riluzole only [N = 6 cases composed of ALS-TDP (n = 4) and ALS-SOD1 (n = 2)]. RESULTS: Our results revealed no significant difference in neuron density or TDP-43 burden in the motor cortex and spinal cord of patients that had received CuATSM compared with patients that had not. In patients that had received CuATSM, p62-immunoreactive astrocytes were observed in the motor cortex and reduced Iba1 density was found in the spinal cord. However, no significant difference in measures of astrocytic activity and SOD1 immunoreactivity was found with CuATSM treatment. DISCUSSION: These findings, in this first postmortem investigation of patients with ALS in CuATSM trials, demonstrate that in contrast to that seen in preclinical models of disease, CuATSM does not significantly alleviate neuronal pathology or astrogliosis in patients with ALS.
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Esclerose Lateral Amiotrófica , Camundongos , Animais , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/patologia , Cobre , Superóxido Dismutase-1 , Riluzol , Superóxido Dismutase , Neurônios Motores/patologia , Medula Espinal/patologia , Proteínas de Ligação a DNA , Camundongos TransgênicosRESUMO
Musculoskeletal disorders are one of the biggest contributors to morbidity and place an enormous burden on the health care system in an aging population. Owing to their immunomodulatory and regenerative properties, mesenchymal stromal/stem cells (MSCs) have demonstrated therapeutic efficacy for treatment of a wide variety of conditions, including musculoskeletal disorders. Although MSCs were originally thought to differentiate and replace injured/diseased tissues, it is now accepted that MSCs mediate tissue repair through secretion of trophic factors, particularly extracellular vesicles (EVs). Endowed with a diverse cargo of bioactive lipids, proteins, nucleic acids and metabolites, MSC-EVs have been shown to elicit diverse cellular responses and interact with many cell types needed in tissue repair. The present review aims to summarize the latest advances in the use of native MSC-EVs for musculoskeletal regeneration, examine the cargo molecules and mechanisms underlying their therapeutic effects, and discuss the progress and challenges in their translation to the clinic.
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Vesículas Extracelulares , Células-Tronco Mesenquimais , Doenças Musculoesqueléticas , Humanos , Idoso , Vesículas Extracelulares/metabolismo , Doenças Musculoesqueléticas/terapia , Imunomodulação , Comunicação Celular , Células-Tronco Mesenquimais/fisiologiaRESUMO
Increasing evidence indicates that dietary nitrate supplementation has the potential to increase muscular power output during skeletal muscle contractions. However, there is still a paucity of data characterizing the impact of different nitrate dosing regimens on nitric oxide bioavailability and its potential ergogenic effects across various population groups. This review discusses the potential influence of different dietary nitrate supplementation strategies on nitric oxide bioavailability and muscular peak power output in healthy adults, athletes, older adults and some clinical populations. Effect sizes were calculated for peak power output and absolute and/or relative nitrate doses were considered where applicable. There was no relationship between the effect sizes of peak power output change following nitrate supplementation and when nitrate dosage when considered in absolute or relative terms. Areas for further research are also recommended including a focus on nitrate dosing regimens that optimize nitric oxide bioavailability for enhancing peak power at times of increased muscular work in a variety of healthy and disease populations.
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Increasing evidence indicates that dietary nitrate supplementation has the potential to increase muscular power output during skeletal muscle contractions. However, there is still a paucity of data characterizing the impact of different nitrate dosing regimens on nitric oxide bioavailability its potential ergogenic effects across various population groups. This narrative review discusses the potential influence of different dietary nitrate supplementation strategies on nitric oxide bioavailability and muscular power output in healthy adults, athletes, older adults and some clinical populations. Areas for further research are also recommended including a focus individualized nitrate dosing regimens to optimize nitric oxide bioavailability and to promote muscular power enhancements in different populations.
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Beta vulgaris , Nitratos , Humanos , Idoso , Óxido Nítrico/metabolismo , Suplementos Nutricionais , Contração Muscular , Disponibilidade Biológica , Músculo Esquelético/metabolismo , Método Duplo-CegoRESUMO
BACKGROUND: Although both EQ-5D-3L(3L) and EQ-5D-5L(5L) have demonstrated good measurement properties in several patient populations, there is currently limited evidence comparing the measurement properties of 3L and 5L in family caregivers (FCs) of cancer patients. PURPOSE: This study aimed to compare the measurement properties of 3L and 5L in a sample of family caregivers of cancer patients. METHODS: A consecutive sample of FCs of cancer patients recruited from three tertiary hospitals were invited to complete the two versions of the EQ-5D in two rounds of interviews. We compared i) the ceiling effect using the McNemar's test, ii) test-retest reliability using intraclass correlation coefficient (ICC) and Cohen's Kappa, iii) convergent validity using Spearman's rank correlation coefficient, iv) known-group validity using F-statistic, v) and discriminant capacity using ordinal logistic regression. RESULTS: A total of 416 FCs completed the baseline questionnaire and 120 caregivers completed the follow-up questionnaire. Ceiling effects were smaller in 5L (12.5%) than in 3L (20.7%). The convergent validity (r = 0.344-0.771), known-groups validity (Fratio5L/3L = 2.06-4.09), discriminant capacity (ES = 0.341-0.396), and test-retest reliability (ICC = 0.725) of the 5L were slightly better than those of the 3L in China. CONCLUSION: The current study found both 3L and 5L to be suitable for use by FCs of cancer patients. However, 5L showed superior measurement properties compared to 3L and therefore could be the preferred instrument when EQ-5D data of cancer patients FCs is required.
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Neoplasias , Qualidade de Vida , Humanos , Cuidadores , Reprodutibilidade dos Testes , População do Leste Asiático , Psicometria , Inquéritos e Questionários , Nível de SaúdeRESUMO
The diuretic effect of the combined furosemide and aminophylline/theophylline among pediatric patients remains unclear. The primary aim of this systematic review was to examine the clinical diuretic effects (urine output and fluid balance) of co-administration of furosemide and aminophylline/theophylline as compared to furosemide alone in pediatric population. Ovid MEDLINE, CENTRAL, and EMBASE were searched from its inception until March 2022 for observational studies and randomized controlled trials (RCTs) comparing the administration of furosemide versus furosemide and aminophylline/theophylline in pediatric population. Case reports, case series, commentaries, letters to editors, systematic reviews, and meta-analyses were excluded. Five articles with a total sample population of 187 patients were included in this systematic review. As compared to the furosemide alone, our pooled data demonstrated that co-administration of furosemide and aminophylline/theophylline was associated with higher urine output (mean difference: 2.91 [90% CI 1.54 to 4.27], p < 0.0001, I2 = 90%) and a more negative fluid balance (mean difference - 28.27 [95% CI: - 46.21 to - 10.33], p = 0.002, I2 = 56%) than those who received furosemide alone. CONCLUSION: This is the first paper summarizing the evidence of combined use of furosemide with aminophylline/theophylline in pediatric population. Our systematic review demonstrated that the co-administration of furosemide and aminophylline/theophylline could potentially yield better diuretic effects of urine output and negative fluid balance than furosemide alone in pediatric patients with fluid overload. Given the substantial degree of heterogeneity and low level of evidence, future adequately powered trials are warranted to provide evidence regarding the combined use of aminophylline/theophylline and furosemide as diuretic in the pediatric population. WHAT IS KNOWN: ⢠Fluid overload is associated with poor prognosis for children in the intensive care unit. ⢠The ineffective result of furosemide alone, even at high dose, as diuretic agent for children with diuretic resistant fluid overload in the intensive care unit. WHAT IS NEW: ⢠This is the first systematic review that compares furosemide alone and co-administration of furosemide and aminophylline/theophylline. ⢠This paper showed potential benefit of co-administration of furosemide and aminophylline/theophylline promoting urine output and negative fluid balance compared to furosemide alone.
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Diuréticos , Teofilina , Criança , Humanos , Diuréticos/farmacologia , Diuréticos/uso terapêutico , Aminofilina/farmacologia , Aminofilina/uso terapêutico , Furosemida/farmacologia , Furosemida/uso terapêuticoRESUMO
Recent reports have acknowledged the underrepresentation of women in the field of dietary nitrate (NO3-) research. Undoubtedly, greater participation from women is warranted to clarify potential sex differences in the responses to dietary NO3- interventions. However, careful consideration for the effects of sex hormones - principally 17ß-estradiol - on endogenous nitric oxide (NO) synthesis and dietary NO3- reductase capacity is necessary for improved interpretation and reproducibility of such investigations. From available literature, we present a narrative review describing how hormonal variations across the menstrual cycle, as well as with menopause, may impact NO biosynthesis catalyzed by NO synthase enzymes and NO3- reduction via the enterosalivary pathway. In doing so, we address methodological considerations related to the menstrual cycle and hormonal contraceptive use relevant for the inclusion of premenopausal women along with factors to consider when testing postmenopausal women. Adherence to such methodological practices may explicate the utility of dietary NO3- supplementation as a means to improve vascular function among women across the lifespan.
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Pesquisa Biomédica/métodos , Menopausa/efeitos dos fármacos , Ciclo Menstrual/efeitos dos fármacos , Nitratos/farmacologia , Suplementos Nutricionais , Estradiol/metabolismo , Feminino , Humanos , Menopausa/metabolismo , Ciclo Menstrual/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico/metabolismo , Fatores SexuaisRESUMO
The objective of this study was to evaluate and compare the psychometric properties of the EQ-5D-Y-3L, EQ-5D-Y-5L, CHU-9D, and PedsQL, in a sample of children and adolescents with osteogenesis imperfecta (OI). A web-based cross-sectional survey was conducted among Chinese children and adolescents with OI in 2021. The EQ-5D-Y-3L, EQ-5D-Y-5L, CHU-9D, and PedsQL were used to assess the health-related quality of life for the participants. Construct validity, including convergent and divergent validity, known-group validity, and test-retest reliability, was examined to assess the psychometric properties of the measures. A total of 157 pediatric OI patients self-completed the questionnaire. Few of them reported the full health status. A strong ceiling effect was observed for all dimensions on the EQ-5D-Y and most on CHU-9D. Most dimensions of the EQ-5D-Y and CHU-9D showed statistically significant correlations with the hypothesized PedsQL subscales. The test-retest reliability for the EQ-5D-Y-3L, EQ-5D-Y-5L, and CHU-9D was acceptable. The EQ-5D-Y-5L showed a better known-group validity than EQ-5D-Y-3L, CHU-9D, and PedsQL in differentiating patients in risk groups. CONCLUSION: The results confirmed that the EQ-5D-Y and CHU-9D are reliable and valid in pediatric OI patients. The EQ-5D-Y-5L performed better than EQ-5D-Y-3L regarding acceptability, convergent validity, and discriminatory power. WHAT IS KNOWN: ⢠Performance of the preference-based measures has never been reported in patients with Osteogenesis imperfecta. WHAT IS NEW: ⢠The EQ-5D-Y demonstrated higher sensitivity and discriminatory power than the CHU-9D in patients with osteogenesis Imperfecta ⢠The EQ-5D-Y-3L performed slightly better than EQ-5D-Y-5L regarding convergent validity and discriminant ability.
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Osteogênese Imperfeita , Qualidade de Vida , Humanos , Adolescente , Criança , Psicometria/métodos , Reprodutibilidade dos Testes , Estudos Transversais , Osteogênese Imperfeita/diagnóstico , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: The clinical efficacy of corticosteroids remains unclear. The primary aim of this systematic review and meta-analysis was to evaluate the use of high-dose versus low- dose corticosteroids on the mortality rate of COVID-19 patients. DESIGN: Systematic review and meta-analysis. SETTING: Electronic search for randomized controlled trials and observational studies (MEDLINE, EMBASE, CENTRAL). PARTICIPANTS: Hospitalized adults ≥ 18 years old who were SARS-CoV-2 PCR positive. INTERVENTIONS: High-dose and low-dose corticosteroids. MEASUREMENTS AND MAIN RESULTS: A total of twelve studies (n=2759 patients) were included in this review. The pooled analysis demonstrated no significant difference in mortality rate between the high-dose and low-dose corticosteroids groups (n=2632; OR: 1.07 [95%CI 0.67, 1.72], p=0.77, I2=76%, trial sequential analysis=inconclusive). No significant differences were observed in the incidence of intensive care unit (ICU) admission rate (n=1544; OR: 0.77[95%CI 0.43, 1.37], p=0.37, I2= 72%), duration of hospital stay (n=1615; MD: 0.53[95%CI -1.36, 2.41], p=0.58, I2=87%), respiratory support (n=1694; OR: 1.51[95%CI 0.77, 2.96], p=0.23, I2=84%), duration of mechanical ventilation (n=419; MD: -1.44[95%CI -4.27, 1.40], p=0.32, I2=93%), incidence of hyperglycemia (n=516, OR: 0.91[95%CI 0.58, 1.43], p=0.68, I2=0%) and infection rate (n=1485, OR: 0.86[95%CI 0.64, 1.16], p=0.33, I2=29%). CONCLUSION: The meta-analysis demonstrated high-dose corticosteroids did not reduce mortality rate. However, high-dose corticosteroids did not pose higher risk of hyperglycemia and infection rate for COVID-19 patients. Due to the inconclusive trial sequential analysis, substantial heterogeneity and low level of evidence, future large-scale randomized clinical trials are warranted to improve the certainty of evidence for the use of high-dose compared to low-dose corticosteroids in COVID-19 patients.
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COVID-19 , Hiperglicemia , Adolescente , Corticosteroides/uso terapêutico , Adulto , Humanos , Respiração Artificial , SARS-CoV-2RESUMO
Dietary nitrate (NO3-) supplementation can reduce the oxygen cost of submaximal exercise, but this has not been reported consistently. We hypothesised that the number of step transitions to moderate-intensity exercise, and corresponding effects on the signal-to-noise ratio for pulmonary VË O2, may be important in this regard. Twelve recreationally active participants were assigned in a randomised, double-blind, crossover design to supplement for 4 days in three conditions: 1) control (CON; water); 2); PL (NO3--depleted beetroot juice); and 3) BR (NO3--rich beetroot juice). On days 3 and 4, participants completed two 6-min step transitions to moderate-intensity cycle exercise. Breath-by-breath VË O2 data were collected and VË O2 kinetic responses were determined for a single transition and when the responses to 2, 3 and 4 transitions were ensemble-averaged. Steady-state VË O2 was not different between PL and BR when the VË O2 response to one-, two- or three-step transition was compared but was significantly lower in BR compared to PL when four-step transitions was considered (PL: 1.33 ± 0.34 vs. BR: 1.31 ± 0.34 L·min-1, P < 0.05). There were no differences in pulmonary VË O2 responses between CON and PL (P > 0.05). Multiple step transitions may be required to detect the influence of NO3- supplementation on steady-state VË O2.
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Beta vulgaris , Nitratos , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego , Tolerância ao Exercício/fisiologia , Humanos , Nitritos , Oxigênio , Consumo de Oxigênio/fisiologia , Troca Gasosa PulmonarRESUMO
The purpose of this study was to investigate effects of concurrent and independent administration of dietary nitrate (NO3-), administered as NO3--rich beetroot juice (BR; ~12.4 mmol of NO3-), and N-acetylcysteine (NAC; 70 mg·kg-1) on physiological responses during prolonged exercise and subsequent high-intensity exercise tolerance. Sixteen recreationally active males supplemented with NO3--depleted beetroot juice (PL) or BR for 6 days and ingested an acute dose of NAC or maltodextrin (MAL) 1 h prior to performing 1 h of heavy-intensity cycling exercise immediately followed by a severe-intensity time-to-exhaustion (TTE) test in four conditions: 1) PL+MAL, 2) PL+NAC, 3) BR+MAL and 4) BR+NAC. Pre-exercise plasma [NO3-] and nitrite ([NO2-]) were elevated following BR+NAC and BR+MAL (both P < 0.01) compared with PL+NAC and PL+MAL; plasma [cysteine] was increased in PL+NAC and BR+NAC (both P < 0.01) compared to PL+MAL. Muscle excitability declined over time during the prolonged cycling bout in all conditions but was better preserved in PL+NAC compared to BR+NAC (P < 0.01) and PL+MAL (P < 0.05). There was no effect of supplementation on subsequent TTE . These findings indicate that co-ingestion of BR and NAC does not appreciably alter physiological responses during prolonged heavy-intensity cycling or enhance subsequent exercise tolerance.
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Acetilcisteína , Suplementos Nutricionais , Exercício Físico , Sucos de Frutas e Vegetais , Nitratos , Extratos Vegetais , Humanos , Masculino , Exercício Físico/fisiologia , Nitratos/sangue , Acetilcisteína/administração & dosagem , Antioxidantes/administração & dosagem , Estudos Cross-Over , Espécies Reativas de Oxigênio , Treino Aeróbico , Consumo de Oxigênio/fisiologia , Nitritos/sangue , Adulto , Extratos Vegetais/farmacologia , Raízes de PlantasRESUMO
OBJECTIVE: Current return-to-sport decisions are primarily based on elapsed time since surgery or injury and strength measures. Given data that show rates of successful return to competitive sport at around 55%, there is strong rationale for adopting tools that will better inform return to sport decisions. The authors' objective was to assess reactive strength as a metric for informing return-to-sport decisions. DESIGN: Case-control design. METHODS: Fifteen elite athletes from national sports teams (23 [6.0] y) in the final phase of their return-to-sport protocol following a unilateral knee injury and 16 age-matched control athletes (22 [4.6] y) performed a unilateral isometric strength test and 24-cm drop jump test. Pairwise comparisons were used to determine differences between legs within groups and differences in interleg asymmetry between groups. RESULTS: Strength measures did not distinguish the control from the rehabilitation group; however, clear differences in the degree of asymmetry were apparent between the control and rehabilitation groups for contact time (Cohen d = 0.56; -0.14 to 1.27; 8.2%; P = .113), flight time (d = 1.10; 0.44 to 1.76; 16.0%; P = .002), and reactive strength index (d = 1.27; 0.50 to 2.04; 22.4%; P = .002). CONCLUSION: Reactive strength data provide insight into functional deficits that persist into the final phase of a return-to-sport protocol. The authors' findings support the use of dynamic assessment tools to inform return-to-sport decisions to limit potential for reinjury.
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Lesões do Ligamento Cruzado Anterior , Reconstrução do Ligamento Cruzado Anterior , Traumatismos do Joelho , Lesões do Ligamento Cruzado Anterior/cirurgia , Estudos de Casos e Controles , Humanos , Volta ao EsporteRESUMO
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is associated with a range of clinical phenotypes and shows progressive degeneration of upper and/or lower motor neurons, and phosphorylated 43 kDa TAR DNA-binding protein (pTDP-43) inclusions in motor and non-motor pathways. Parkinsonian features have been reported in up to 30% of ALS patients, and Lewy bodies, normally associated with Lewy body disease (LBD), have been reported in a small number of ALS cases, with unknown clinical relevance. This study investigates the prevalence of clinically relevant LBD in a prospectively studied ALS cohort to determine whether concomitant pathology contributes to the clinical heterogeneity. METHODS: All ALS cases held by the New South Wales Brain Bank (n = 97) were screened for coexisting LBD consistent with clinical disease (Braak ≥ stage IV). Relevant clinical and genetic associations were determined. RESULTS: Six cases had coexisting LBD Braak ≥ stage IV pathology. The age at symptom onset (69 ± 7 years) and disease duration (4 ± 3 years) in ALS cases with coexisting LBD did not differ from ALS cases. Three patients had lower limb onset and two patients had bulbar onset. Two patients developed the clinical features of Parkinson's disease, with one receiving a dual diagnosis. All cases had no known relevant family history or genetic abnormalities. CONCLUSION: The prevalence of clinically relevant LBD pathology in ALS is higher than in the general population, and has implications for clinical and neuropathological diagnoses and the identification of biomarkers.
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Esclerose Lateral Amiotrófica , Doença por Corpos de Lewy , Transtornos Parkinsonianos , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/genética , Proteínas de Ligação a DNA/genética , Humanos , Corpos de Inclusão , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/epidemiologia , Doença por Corpos de Lewy/genética , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/epidemiologia , Transtornos Parkinsonianos/genéticaRESUMO
OBJECTIVES: This study aimed to synthesize and evaluate published evidence on the measurement properties of the EQ VAS, a component of all EQ-5D questionnaires. METHODS: This systematic review followed the Consensus-Based Standards for the Selection of Health Measurement Instruments guidelines. Five electronic databases were searched for EQ-5D-3L and EQ-5D-5L validation articles published from January 1, 2009, to November 5, 2019. Evidence for construct validity, test-retest reliability, and responsiveness was extracted from individual studies before being aggregated for evaluation of the populations represented by the studied samples. Multivariable logistic meta-regression was conducted to explore the effects of potential covariates on construct validity. RESULTS: A total of 50 articles containing 488 studies, using samples drawn from 12 different populations, were identified. Generally, the quality of evidence was high for construct validity studies (n = 397) but only moderate for both test-retest reliability studies (n = 21) and responsiveness studies (n = 70). "Sufficient" construct validity of EQ VAS was found in 8 of 12 populations, "sufficient" test-retest reliability was found in 3 of 11 populations, and "sufficient" responsiveness was found in 5 of 12 populations. Meta-regression analyses suggested that construct validity studies from the Asian-Pacific region were more likely to show a negative rating compared with studies from Europe and North America. CONCLUSION: The EQ VAS exhibits "sufficient" construct validity, "inconsistent" test-retest reliability, and "inconsistent" responsiveness across a broad range of populations. Additional studies are needed to explore the suboptimal validity of the EQ VAS in the Asian-Pacific region, whereas more high-quality validation studies are needed to assess its reliability and responsiveness.
Assuntos
Saúde Global , Nível de Saúde , Psicometria/estatística & dados numéricos , Qualidade de Vida , Inquéritos e Questionários/normas , Ásia , Europa (Continente) , Humanos , América do Norte , Reprodutibilidade dos TestesRESUMO
CD163 facilitates regulation and resolution of inflammation and removal of free hemoglobin and is highly expressed in myeloid cells from patients with inflammatory disorders, such as systemic juvenile idiopathic arthritis (SJIA) and macrophage activation syndrome (MAS). Our recent studies indicate that regulation of CD163 mRNA expression is a key functional property of polarized monocytes and macrophages and is mediated at the transcriptional and posttranscriptional level, including via microRNAs. The goal of the current study is to develop a multiparameter flow cytometry panel incorporating detection of CD163 mRNA for polarized monocyte and macrophage populations in disorders such as SJIA and MAS. THP-1 cells and CD14+ human monocytes were stained using fluorochrome-conjugated Abs to myeloid surface markers, along with CD163 mRNA. Staining for mRNA could reliably detect CD163 expression while simultaneously detecting different macrophage populations using Abs targeting CD14, CD64, CD80, CD163, and CD209. This approach was found to be highly sensitive for increased mRNA expression when macrophages were polarized with IL-10 [M(IL-10)], with a strong signal over a broad range of IL-10 concentrations, and showed distinct kinetics of CD163 mRNA and protein induction upon IL-10 stimulation. Finally, this panel demonstrated clear changes in polarization markers in unstimulated monocytes from patients with SJIA and MAS, including upregulated CD163 mRNA and increased CD64 expression. This approach represents a robust and sensitive system for RNA flow cytometry, useful for studying CD163 expression as part of a multimarker panel for human monocytes and macrophages, with broad applicability to the pathogenesis of hyperinflammatory diseases.