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BACKGROUND: Dry powder inhalers (DPIs) rely on both internal resistance and patients' inspiratory capacity for effective operation. Optimal inspiratory technique is crucial for DPI users. This study assessed the accuracy and repeatability of two available devices, PF810® and In-Check DIAL®, and analyzed their measurement errors and consistency in detecting inspiratory capacity. METHODS: The accuracy and repeatability of peak inspiratory flow (PIF) and forced inspiratory vital capacity (FIVC) against various internal resistances of the two devices were assessed using standard waveforms generated by a breathing simulator. The agreement of PIF measurements between the two devices in healthy volunteers and chronic obstructive pulmonary disease (COPD) patients was analyzed with the intraclass correlation coefficient and Bland-Altman graphical analysis. RESULTS: PF810® showed great accuracy and repeatability in measuring PIF, except for square waveforms at the lowest flow rate (20 L/min). In-Check DIAL® exhibited poor accuracy against high resistance levels. In scenarios with no resistance, In-Check DIAL® had significantly smaller measurement errors than PF810®, but larger errors against high resistance levels. The two devices showed excellent agreement (ICC > 0.80, P < 0.05), except for healthy volunteers against medium to high resistance (R3-R5) where the ICC was insignificant. Bland-Altman plots indicated small disagreements between the two devices for both healthy volunteers and COPD patients. CONCLUSIONS: In-Check DIAL® exhibited poor accuracy and larger measurement errors than PF810® when detecting PIFs against higher internal resistances. However, its good performance against lower internal resistances, along with its cost-effectiveness and convenience made it appropriate for primary care. PF810® showed good accuracy and repeatability and could detect additional parameters of inspiratory capacity beyond PIF, though required further studies to confirm its clinical benefits.
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Inhaladores de Polvo Seco , Capacidad Inspiratoria , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Reproducibilidad de los Resultados , Diseño de Equipo , Adulto Joven , Administración por Inhalación , Capacidad Vital , Voluntarios SanosRESUMEN
OBJECTIVE: This study assessed the cellular composition and effects of leukocyte-platelet-rich fibrin (L-PRF) exudate on whole blood platelets from healthy volunteers. Key objectives included evaluating leukocyte subpopulations, platelet activation markers, platelet-leukocyte interactions and quantifying inflammatory cytokines within the L-PRF exudate. MATERIALS AND METHODS: L-PRF was obtained from 20 healthy donors. Flow cytometry methodologies were used to assess intracellular calcium kinetics and activated GPIIbIIIa, and P-selectin expression. Leukocyte subpopulations and platelet-leukocyte interactions were characterized using monoclonal antibodies. Inflammatory cytokines (IL-8, IL-1ß, IL-6, IL-10, TNF, IL-12p70) within L-PRF exudate were quantified using a cytometric bead array. RESULTS: The expression of activated GPIIbIIIa, and P-selectin exhibited a significant increase (p < 0.001) when L-PRF exudate was added to platelets of whole blood. Regarding intracellular Ca2+ mobilization, the L-PRF exudate elicited significant responses (p < 0.001). L-PRF exudate contained different leukocytes populations, being TCD4 + the most representative of T cells. It was possible to stablish a profile of cytokines produced by the L-PRF exudate, with human IL-8 cytokine exhibiting the highest average (16.90 pg/mL). CONCLUSIONS: Despite the study limitations, the research yielded important insights: 1- L-PRF exudate can stimulate platelet activation, essential in healing, tissue inflammation and remodeling. 2-The presence of leukocyte subpopulations within L-PRF exudate reflexes its complexity and potential to enhance immune responses. 3-The analysis of inflammatory cytokines within L-PRF exudate revealed its immunomodulatory potential. These findings are valuable evidences for understanding the potential role of L-PRF exudate in regenerative dentistry and medicine, offering innovative therapeutic strategies. CLINICAL RELEVANCE: This research highlights crucial aspects that could significantly influence the clinical use of L-PRF exudate in the oral cavity. The findings support the application of L-PRF exudate in both surgical and regenerative dentistry, facilitating the development of innovative therapeutic strategies to enhance patient outcomes.
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Plaquetas , Citocinas , Exudados y Transudados , Citometría de Flujo , Fibrina Rica en Plaquetas , Humanos , Masculino , Citocinas/metabolismo , Femenino , Adulto , Voluntarios Sanos , Activación Plaquetaria , Leucocitos , Biomarcadores/sangreRESUMEN
BACKGROUND: Prefabricated orthotic insoles are widely commercially available for self-selection to treat foot and lower-body musculoskeletal pain, without requiring advice from health care professionals. Although they are generally designed to mimic traditional design features of custom-made orthotics used in clinical practice, the effects of prefabricated insoles on plantar pressure distribution are poorly understood. OBJECTIVE: This investigation aimed to evaluate and directly compare the effects of a range of 6 different commercially available prefabricated orthotic insole designs on plantar pressure in healthy individuals. METHODS: This was a single-center, randomized, open-label, crossover investigation. In-shoe dynamic pressure (F-scan) was investigated in 24 healthy subjects with normal foot posture, wearing standard shoes alone and in combination with 6 different orthotic insoles, consecutively, measured on a single day. The biomechanical impact of each insole was determined by the statistical significance of changes from baseline measurements (standard shoe alone). RESULTS: Insoles with heel cups and medial arch geometries consistently increased contact area at medial arch and whole-foot regions and reduced both plantar peak pressure (PP) and pressure time integral at medial arch and heel regions. CONCLUSIONS: This investigation has aided in further understanding the mode of action of prefabricated insoles in a healthy population. The insoles in this study redistributed plantar pressure at key regions of the foot, based on design features common to prefabricated insoles. Prefabricated orthotic insoles represent an easily accessible means of reducing lower-body musculoskeletal stress for those who spend prolonged periods of time on their feet.
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Estudios Cruzados , Diseño de Equipo , Ortesis del Pié , Pie , Presión , Humanos , Masculino , Adulto , Femenino , Adulto Joven , Voluntarios Sanos , Fenómenos Biomecánicos , Zapatos , Soporte de Peso/fisiologíaRESUMEN
In humans, α-tocopherol (α-TOC) is mainly stored in adipose tissue, where it participates in preventing damages induced by inflammation and reactive oxygen species. Factors, including genetic ones, that explain adipose tissue α-TOC concentration remain poorly understood. This study, therefore, aimed to characterize the interindividual variability of adipose tissue α-TOC concentration in healthy individuals and to identify single nucleotide polymorphisms (SNPs) associated with it. The study used a randomized cross-over design with 42 healthy adult males. α-TOC concentration was measured in fasting plasma and periumbilical adipose tissue samples, both at fast and 8 h after consumption of three standard meals. Partial least squares (PLS) regression was performed to identify SNPs associated with the interindividual variability of adipose tissue α-TOC concentration. Adipose tissue α-TOC concentration was not associated with fasting plasma concentration (Pearson's r = 0.24, 95% CI: [-0.08, 0.51]). There was a high interindividual variability of adipose tissue α-TOC concentration (CV = 61%). A PLS regression model comprising 10 SNPs in five genes (PPARG, ABCA1, BUD13, CD36, and MGLL) explained 60% (adjusted R2) of the variability of this concentration. The interindividual variability of adipose tissue α-TOC concentration in humans is due, at least partly, to SNPs in genes involved in α-TOC and triglyceride metabolism.
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Estudios Cruzados , Polimorfismo de Nucleótido Simple , Grasa Subcutánea , alfa-Tocoferol , Humanos , Masculino , alfa-Tocoferol/sangre , alfa-Tocoferol/metabolismo , Adulto , Grasa Subcutánea/metabolismo , Adulto Joven , Ayuno , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Antígenos CD36/genética , Antígenos CD36/metabolismo , Voluntarios SanosRESUMEN
OBJECTIVE: The study aims to explore the relationship between modifiable lifestyle factors (physical activity, sedentary time, body composition, muscle strength) and mental health, and predict future changes in mental health. METHODS: A cross-sectional survey was conducted on 133 men (age: 29.03 ± 6.605 years, BMI: 23.58 ± 2.688 kg/m²) to assess baseline body composition, muscle strength, sedentary time, and mental health, with follow-up at 3 months. F-tests were employed to compare the differences in mental health on sedentary time and body composition variables. Spearman correlation analysis was used to examine correlations between variables. RESULTS: Spearman's correlation analysis showed that sedentary time, muscle strength and mental health of the subjects were significantly correlated. BMI, BFM, BFMI, PBF were higher in subjects with ≥ 4 h of sedentary time than in the other two shorter sedentary time groups. Subjects with higher PBF (p = 0.047, η2 = 0.030) and BFM (p = 0.032, η2 = 0.035) had severer depression. Subjects who sat for ≥ 4 h at a time were more severely depressed than those who sat for 2-4 h (p = 0.020). Change in depression was significantly negatively correlated with BMI, BFM, BFMI and PBF. Subjects with higher PBF (p = 0.023, η2 = 0.050) and BFM (p = 0.005, η2 = 0.075) at the baseline had less change in depression. CONCLUSION: A Significant correlation was found between sedentary time, body composition and mental health, and baseline body composition predicted changes in mood three months later.
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Estilo de Vida , Salud Mental , Estudios Transversales , Conducta Sedentaria , Composición Corporal , Depresión/psicología , Voluntarios Sanos/psicología , Humanos , Masculino , Adulto Joven , Adulto , Fuerza Muscular/fisiología , TiempoRESUMEN
Ruzotolimod (Toll-like receptor 7 (TLR7) agonist, RG7854) is an oral, small molecule immuno-modulator activating the TLR 7 and is being evaluated in patients with CHB. As with other TLR7 agonists, the study drug-related adverse events of flu-like symptoms have been reported in some participants during phase I studies with ruzotolimod. An exploratory analysis of the relationship between pharmacokinetic (PK)/pharmacodynamic (PD) and flu-like symptoms was performed in participants from two phase I studies including both healthy volunteers and NUC-suppressed CHB patients who received either single or multiple ascending doses of orally administered ruzotolimod. Linear and logistic regression were used to explore potential relationships between dose, flu-like symptoms, PK, and PD. Generalized linear regression was performed to predict the probability of flu-like symptoms of all intensities at different RO7011785 (the active metabolite of the double prodrug ruzotolimod) PK exposure. This analysis showed that single or multiple doses of ruzotolimod at ⩾100 mg, the immune PD (IFN-α, neopterin, IP-10, and the transcriptional expression of ISG15, OAS-1, MX1, and TLR7) responses increase with the RO7011785 PK exposure, which increases linearly with the doses from 3 mg to 170 mg of ruzotolimod. The analysis also showed that the probability of flu-like symptoms occurrence increases with PD responses (IFN-α and IP-10). Dose reduction of ruzotolimod can be an effective way to reduce the magnitude of PD response, thus reducing the probability of study drug-related flu-like symptoms occurrence at all intensity in the participants who are highly sensitive to PD activation and intolerant to flu-like symptoms.
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Voluntarios Sanos , Hepatitis B Crónica , Receptor Toll-Like 7 , Humanos , Receptor Toll-Like 7/agonistas , Masculino , Adulto , Femenino , Persona de Mediana Edad , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/virología , Hepatitis B Crónica/sangre , Adulto Joven , Antivirales/farmacocinética , Antivirales/administración & dosificación , Antivirales/efectos adversos , Gripe Humana/tratamiento farmacológico , Gripe Humana/inmunología , Relación Dosis-Respuesta a Droga , Adolescente , Administración Oral , Compuestos OrgánicosRESUMEN
OBJECTIVES: This study aims to investigate the previously reported dependency of intravoxel incoherent motion (IVIM) parameters on simultaneous multislice (SMS) acquisition and repetition time (TR). This includes the influence of slice thickness, slice gaps, and slice order on measured IVIM parameters. MATERIALS AND METHODS: Diffusion-weighted imaging (DWI) of the liver was performed on 10 healthy volunteers (aged 20-30 years) at 3T with a slice thickness of 5 mm, a slice gap of 5 mm, and a linear slice order. Diffusion-weighted images were acquired with 19 b-values (0-800 s/mm2) using both conventional slice excitation with an acceleration factor of one (AF1) and SMS excitation with an acceleration factor of three (AF3). Each of these measurements were carried out with two repetition times (TRs)- 1,300 ms (prefix s) and 4,500 ms (prefix l)-resulting in four different combinations: sAF1, sAF3, lAF1, and lAF3. Five volunteers underwent additional measurements using a 10 mm slice thickness and with AF1. Median signal values in the liver were used to determine the biexponential IVIM parameters. Statistical significances were assessed using the Kruskal-Wallis test, Wilcoxon signed-rank test, and Student's t-test. In-silico investigations were also used to interpret the data. RESULTS: There were no significant differences between the biexponential IVIM parameters acquired from sAF1, sAF3, lAF1, and lAF3. Median values of the perfusion fraction f were as follows: 29.9% (sAF1), 26.9% (sAF3), 28.1% (lAF1), and 27.5% (lAF3). In the 10 mm-thick slices, f decreased from 31.3% (lAF1) to 27.4% (sAF1) (p = 0.141). CONCLUSION: The slice excitation mode did not appear to have any significant influence on the biexponential IVIM parameters. However, our simulations, as well as values reported from previous publications, show that slice thickness, slice gaps, and slice order are relevant and should thus be reported in IVIM studies.
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Imagen de Difusión por Resonancia Magnética , Hígado , Humanos , Adulto , Hígado/diagnóstico por imagen , Masculino , Femenino , Adulto Joven , Imagen de Difusión por Resonancia Magnética/métodos , Movimiento (Física) , Procesamiento de Imagen Asistido por Computador/métodos , Voluntarios SanosRESUMEN
Cells exposed to stressors of various origin activate protective mechanisms that include the expression of heat shock proteins (Hsps)/molecular chaperones belonging to several families. Well-characterized inducible Hsp70 is present in all human cell-types and biological fluids, including blood, urine, and saliva. The presence of anti-Hsp70 autoantibodies in the serum of healthy individuals has already been confirmed, and their elevated titers positively correlated with the severity of several pathological conditions, including coeliac disease and dermatitis herpetiformis - a cutaneous manifestation of coeliac disease. Here, using an indirect enzyme-linked immunosorbent assay, we demonstrate, for the first time, that anti-Hsp70 autoantibodies are present in the saliva and urine of healthy individuals. Although the occurrence of anti-Hsp70 autoantibodies in the biological fluids of healthy individuals is intriguing, their physiological role is currently unknown. It is believed that antibodies reacting with self-molecules present in the serum of healthy individuals are part of natural autoantibody pool with multiple regulatory functions. On the other hand, some autoantibodies (e.g., typical of autoimmune bullous skin diseases or systemic lupus erythematosus) may be present before the onset of the disease and serve as specific predictive biomarkers. Therefore, we would like to initiate a discussion or future research direction on the use of anti-Hsp70 autoantibodies as a potential "biomarker" in the diagnosis or prediction of autoimmune diseases. Our findings can be considered in biomedical research to develop noninvasive, inexpensive and easy-to-use tests. Nevertheless, large-scale comparative studies should be initiated, involving the collection and analysis of biological samples such as saliva or urine from patients suffering from autoimmune diseases or other inflammatory or neoplastic diseases, to determine whether the levels of anti-Hsp70 autoantibodies are indeed elevated and whether they correlate with the clinical picture of any disease or established biomarkers.
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Autoanticuerpos , Proteínas HSP70 de Choque Térmico , Saliva , Humanos , Saliva/inmunología , Saliva/metabolismo , Proteínas HSP70 de Choque Térmico/inmunología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Femenino , Adulto , Masculino , Biomarcadores/orina , Persona de Mediana Edad , Ensayo de Inmunoadsorción Enzimática , Voluntarios SanosRESUMEN
Transcutaneous spinal stimulation (TSS) is a promising rehabilitative intervention to restore motor function and coordination for individuals with spinal cord injury (SCI). The effects of TSS are most commonly assessed by evaluating muscle response to stimulation using surface electromyography (sEMG). Given the increasing use of robotic devices to deliver therapy and the emerging potential of hybrid rehabilitation interventions that combine neuromodulation with robotic devices, there is an opportunity to leverage the on-board sensors of the robots to measure kinematic and torque changes of joints in the presence of stimulation. This paper explores the potential for robotic assessment of the effects of TSS delivered to the cervical spinal cord. We used a four degree-of-freedom exoskeleton to measure the torque response of upper limb (UL) joints during stimulation, while simultaneously recording sEMG. We analyzed joint torque and electromyography data generated during TSS delivered over individual sites of the cervical spinal cord in neurologically intact participants. We show that site-specific effects of TSS are manifested not only by modulation of the amplitude of spinally evoked motor potentials in UL muscles, but also by changes in torque generated by individual UL joints. We observed preferential resultant action of proximal muscles and joints with stimulation at the rostral site, and of proximal joints with rostral-lateral stimulation. Robotic assessment can be used to measure the effects of TSS, and could be integrated into complex control algorithms that govern the behavior of hybrid neuromodulation-robotic systems.
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Electromiografía , Dispositivo Exoesqueleto , Robótica , Traumatismos de la Médula Espinal , Torque , Extremidad Superior , Humanos , Robótica/instrumentación , Masculino , Adulto , Traumatismos de la Médula Espinal/rehabilitación , Femenino , Fenómenos Biomecánicos , Músculo Esquelético/fisiología , Médula Cervical , Voluntarios Sanos , Estimulación de la Médula Espinal/instrumentación , Estimulación de la Médula Espinal/métodos , Adulto Joven , Estimulación Eléctrica Transcutánea del Nervio/instrumentación , Estimulación Eléctrica Transcutánea del Nervio/métodos , Vértebras Cervicales , AlgoritmosRESUMEN
Goal functions make virtual goal-oriented motor tasks easier to analyze and manipulate by explicitly linking movement to outcome. However, they have only been used to study constrained (e.g., planar) upper limb movements. We present a design framework for integrating goal functions with unconstrained postural and upper limb movements in a virtual reality (VR) device. VR tasks designed with the framework can mimic unconstrained natural motions and thus train a range of functional movements yet remain analytically tractable. We created three in-place VR motor tasks: a bow-and-arrow, a reach-and-strike, and a punching bag task. Each task was adjusted to subject-specific workspace limits and anthropometrics. We studied the effects of 3 days of practice and 3 reach/lean distances on task performance in 12 healthy adults. Subjects performed all tasks on day 1 with moderate proficiency and improved with practice at all reach/lean distances. Task-specific results showed that performance decreased and movement variability increased near the edge of the reaching workspace; viewing angles and the imperfect depth cues in VR likely led to biases in performance and practice could attenuate the former effect; in reach-and-strike, subjects learned movement patterns similar to those seen in a real-world striking sport. These results show that our framework can deliver tasks useful for analyzing and training motor performance and can guide future in-place motor training. Post-hoc, we demonstrated the feasibility of generalizable methods that adjust required movement speeds and task difficulty for impaired populations.
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Objetivos , Movimiento , Desempeño Psicomotor , Realidad Virtual , Humanos , Masculino , Femenino , Adulto , Adulto Joven , Movimiento/fisiología , Desempeño Psicomotor/fisiología , Extremidad Superior/fisiología , Voluntarios Sanos , Fenómenos Biomecánicos , Análisis y Desempeño de Tareas , Postura/fisiología , AlgoritmosRESUMEN
We have earlier established a direct measurement method for assessing stool physical consistency using a texture analyzer (TAXT). The present study aimed to evaluate the stool softening effect of Lacticaseibacillus paracasei strain Shirota (LcS) using TAXT in a double-blind, randomized, placebo-controlled study. Sixty-four healthy participants with a Bristol stool form scale (BSFS) 1/2 ≥ 50% during screening consumed fermented milk containing LcS or a placebo beverage daily for 8 weeks. Stool consistency and water content were determined using TAXT and a lyophilizer, respectively. Participants evaluated their defecation using the BSFS. Stool consistency evaluated by a texture analyzer (TAXT) in the LcS group tended to be softer than that in the placebo group (p = 0.052). Subgroup analyses (TAXT value at baseline ≥ 4.5) showed that stool consistency was significantly softer in the LcS group (p = 0.014). Stool water content was also significantly higher in the LcS group than in the placebo group, but the proportion of normal stools was not statistically significant. We were unable to find evidence for the softening effect of LcS under the present study's conditions. However, its efficacy may be confirmed by targeting participants with physically hard stools and TAXT values ≥ 4.5.
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Defecación , Heces , Lacticaseibacillus paracasei , Probióticos , Humanos , Método Doble Ciego , Heces/química , Heces/microbiología , Masculino , Femenino , Adulto , Probióticos/administración & dosificación , Lacticaseibacillus paracasei/fisiología , Voluntarios Sanos , Persona de Mediana Edad , Adulto Joven , Productos Lácteos CultivadosRESUMEN
Ceramides are essential lipids for skin barrier function, and various classes and species exist in the human stratum corneum (SC). To date, the relationship between skin conditions and ceramide composition in healthy individuals has remained largely unclear. In the present study, we measured six skin condition parameters (capacitance, transepidermal water loss, scaliness, roughness, multilayer exfoliation, and corneocyte cell size) for the SC of the cheeks and upper arms of 26 healthy individuals and performed correlation analyses with their SC ceramide profiles, which we measured via liquid chromatography-tandem mass spectrometry. In the cheeks, high levels and/or ratios of two free ceramide classes containing an extra hydroxyl group in the long-chain moiety and a protein-bound ceramide class containing 6-hydroxysphingosine correlated with healthy skin conditions. In contrast, the ratios of two other free ceramide classes, both containing sphingosine, and a protein-bound ceramide class containing 4,14-sphingadiene correlated with unhealthy skin conditions, as did shortening of the carbon chain of the fatty acid portion of two ceramide classes containing non-hydroxy fatty acids. Thus, our findings help to elucidate the relationship between skin conditions and ceramide composition.
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Ceramidas , Epidermis , Humanos , Ceramidas/metabolismo , Ceramidas/análisis , Femenino , Masculino , Epidermis/metabolismo , Adulto , Persona de Mediana Edad , Piel/metabolismo , Voluntarios Sanos , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
BACKGROUND: Increasing functional residual capacity (FRC) or tidal volume (VT) reduces airway resistance and attenuates the response to bronchoconstrictor stimuli in animals and humans. What is unknown is which one of the above mechanisms is more effective in modulating airway caliber and whether their combination yields additive or synergistic effects. To address this question, we investigated the effects of increased FRC and increased VT in attenuating the bronchoconstriction induced by inhaled methacholine (MCh) in healthy humans. METHODS: Nineteen healthy volunteers were challenged with a single-dose of MCh and forced oscillation was used to measure inspiratory resistance at 5 and 19 Hz (R5 and R19), their difference (R5-19), and reactance at 5 Hz (X5) during spontaneous breathing and during imposed breathing patterns with increased FRC, or VT, or both. Importantly, in our experimental design we held the product of VT and breathing frequency (BF), i.e, minute ventilation (VE) fixed so as to better isolate the effects of changes in VT alone. RESULTS: Tripling VT from baseline FRC significantly attenuated the effects of MCh on R5, R19, R5-19 and X5. Doubling VT while halving BF had insignificant effects. Increasing FRC by either one or two VT significantly attenuated the effects of MCh on R5, R19, R5-19 and X5. Increasing both VT and FRC had additive effects on R5, R19, R5-19 and X5, but the effect of increasing FRC was more consistent than increasing VT thus suggesting larger bronchodilation. When compared at iso-volume, there were no differences among breathing patterns with the exception of when VT was three times larger than during spontaneous breathing. CONCLUSIONS: These data show that increasing FRC and VT can attenuate induced bronchoconstriction in healthy humans by additive effects that are mainly related to an increase of mean operational lung volume. We suggest that static stretching as with increasing FRC is more effective than tidal stretching at constant VE, possibly through a combination of effects on airway geometry and airway smooth muscle dynamics.
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Broncoconstricción , Cloruro de Metacolina , Volumen de Ventilación Pulmonar , Humanos , Broncoconstricción/efectos de los fármacos , Broncoconstricción/fisiología , Volumen de Ventilación Pulmonar/fisiología , Volumen de Ventilación Pulmonar/efectos de los fármacos , Masculino , Femenino , Adulto , Adulto Joven , Cloruro de Metacolina/administración & dosificación , Broncoconstrictores/administración & dosificación , Pruebas de Provocación Bronquial/métodos , Capacidad Residual Funcional/fisiología , Capacidad Residual Funcional/efectos de los fármacos , Voluntarios Sanos , Resistencia de las Vías Respiratorias/efectos de los fármacos , Resistencia de las Vías Respiratorias/fisiología , Pulmón/efectos de los fármacos , Pulmón/fisiología , Volumen Espiratorio Forzado/fisiología , Volumen Espiratorio Forzado/efectos de los fármacosRESUMEN
Introduction: Chagas disease, caused by the Trypanosoma cruzi parasite infection, is a potentially life-threatening neglected tropical disease with a worldwide distribution. During the chronic phase of the disease, there exists a fragile balance between the host immune response and parasite replication that keeps patients in a clinically-silent asymptomatic stage for years or even decades. However, in 40% of patients, the disease progresses to clinical manifestations mainly affecting and compromising the cardiac system. Treatment is recommended in the chronic phase, although there are no early markers of its effectiveness. The aim of this study is to identify differential expression changes in genes involved in the immune response in antigen-restimulated PBMC from chronic patients with Chagas disease due to benznidazole treatment. Methods: Thus, high-throughput real-time qPCR analysis has been performed to simultaneously determine global changes in the expression of 106 genes involved in the immune response in asymptomatic (IND) and early cardiac manifestations (CCC I) Chagas disease patients pre- and post-treatment with benznidazole. Results and discussion: The results revealed that 7 out of the 106 analyzed genes were differentially expressed (4 up- and 3 downregulated) after treatment in IND patients and 15 out of 106 (3 up- and 12 downregulated) after treatment of early cardiac Chagas disease patients. Particularly in CCC I patients, regulation of the expression level of some of these genes towards a level similar to that of healthy subjects suggests a beneficial effect of treatment and supports recommendation of benznidazole administration to early cardiac Chagas disease patients. The data obtained also demonstrated that both in asymptomatic patients and in early cardiac chronic patients, after treatment with benznidazole there is a negative regulation of the proinflammatory and cytotoxic responses triggered as a consequence of T. cruzi infection and the persistence of the parasite. This downregulation of the immune response likely prevents marked tissue damage and healing in early cardiac patients, suggesting its positive effect in controlling the pathology.
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Enfermedad de Chagas , Nitroimidazoles , Trypanosoma cruzi , Humanos , Nitroimidazoles/uso terapéutico , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/inmunología , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/genética , Adulto , Masculino , Femenino , Persona de Mediana Edad , Tripanocidas/uso terapéutico , Tripanocidas/farmacología , Leucocitos Mononucleares/inmunología , Enfermedad Crónica , Perfilación de la Expresión Génica , Voluntarios Sanos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Visual feedback gain is a crucial factor influencing the performance of precision grasping tasks, involving multiple brain regions of the visual motor system during task execution. However, the dynamic changes in brain network during this process remain unclear. The aim of this study is to investigate the impact of changes in visual feedback gain during precision grasping on brain network dynamics. Sixteen participants performed precision grip tasks at 15% of MVC under low (0.1°), medium (1°), and high (3°) visual feedback gain conditions, with simultaneous recording of EEG and right-hand precision grip data during the tasks. Utilizing electroencephalogram (EEG) microstate analysis, multiple parameters (Duration, Occurrence, Coverage, Transition probability(TP)) were extracted to assess changes in brain network dynamics. Precision grip accuracy and stability were evaluated using root mean square error(RMSE) and coefficient of variation(CV) of grip force. Compared to low visual feedback gain, under medium/high gain, the Duration, Occurrence, and Coverage of microstates B and D increase, while those of microstates A and C decrease. The Transition probability from microstates A, C, and D to B all increase. Additionally, RMSE and CV of grip force decrease. Occurrence and Coverage of microstates B and C are negatively correlated with RMSE and CV. These findings suggest that visual feedback gain affects the brain network dynamics during precision grasping; moderate increase in visual feedback gain can enhance the accuracy and stability of grip force, whereby the increased Occurrence and Coverage of microstates B and C contribute to improved performance in precision grasping. Our results play a crucial role in better understanding the impact of visual feedback gain on the motor control of precision grasping.
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Electroencefalografía , Retroalimentación Sensorial , Fuerza de la Mano , Desempeño Psicomotor , Humanos , Retroalimentación Sensorial/fisiología , Fuerza de la Mano/fisiología , Masculino , Adulto Joven , Adulto , Femenino , Desempeño Psicomotor/fisiología , Red Nerviosa/fisiología , Voluntarios Sanos , Algoritmos , Encéfalo/fisiologíaRESUMEN
Purpose To compare parameters of left ventricular (LV) and right ventricular (RV) volume and function between a commercially available 0.55-T low-field-strength cardiac cine MRI scanner and a 1.5-T scanner. Materials and Methods In this prospective study, healthy volunteers (May 2022 to July 2022) underwent same-day cine imaging using both scanners (0.55 T, 1.5 T). Volumetric and functional parameters were assessed by two experts. After analyzing the results of a blinded crossover reader study of the healthy volunteers, 20 participants with clinically indicated cardiac MRI were prospectively included (November 2022 to February 2023). In a second blinded expert reading, parameters from clinical 1.5-T scans in these participants were compared with those same-day 0.55-T scans. Results are displayed as Bland-Altman plots. Results Eleven healthy volunteers (mean age: 33 years [95% CI: 27, 40]; four of 11 [36%] female, seven of 11 [64%] male) were included. Very strong mean correlation was observed (r = 0.98 [95% CI: 0.97, 0.98]). Average deviation between MRI systems was 1.6% (95% CI: 0.3, 2.9) for both readers. Twenty participants with clinically indicated cardiac MRI were included (mean age: 55 years [95% CI: 48, 62], six of 20 [30%] female, 14 of 20 [70%] male). Mean correlation was very strong (r = 0.98 [95% CI: 0.97, 0.98]). LV and RV parameters demonstrated an average deviation of 1.1% (95% CI: 0.1, 2.1) between MRI systems. Conclusion Cardiac cine MRI at 0.55 T yielded comparable results for quantitative biventricular volumetric and functional parameters compared with routine imaging at 1.5 T, if acquisition time is doubled. Keywords: Cardiac, Comparative Studies, Heart, Cardiovascular MRI, Cine, Myocardium Supplemental material is available for this article. ©RSNA, 2024.
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Ventrículos Cardíacos , Imagen por Resonancia Cinemagnética , Humanos , Imagen por Resonancia Cinemagnética/métodos , Imagen por Resonancia Cinemagnética/instrumentación , Femenino , Masculino , Adulto , Estudios Prospectivos , Ventrículos Cardíacos/diagnóstico por imagen , Voluntarios Sanos , Estudios CruzadosRESUMEN
Background: Management of hypertension and hyperlipidemia, which are common comorbid risk factors for cardiovascular diseases, require multiple medications. The development of a fixed-dose combination (FDC) containing ezetimibe, rosuvastatin, telmisartan, and amlodipine aims to enhance patient adherence and persistence, but the potential interactions among the four medications have not been studied. This study aimed to evaluate the pharmacokinetic (PK) interactions between the FDC of ezetimibe/rosuvastatin 10/20 mg (ER) and the FDC of telmisartan/amlodipine 80/5 mg (TA). Methods: An open-label, single-sequence, three-period, three-treatment crossover study was conducted in healthy male subjects. All subjects received ER for 7 days, TA for 9 days and ER combined with TA for 7 days during each treatment period. For PK analysis of total/free ezetimibe, rosuvastatin, telmisartan, and amlodipine, serial blood samples were collected for 24 hours at steady state. Safety profiles were assessed throughout the study. Results: Thirty-eight subjects were enrolled, and 34 subjects completed the study. The systemic exposure to each active ingredient after coadministration of the two FDCs was similar to that after each FDC alone. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration (µg/L) and the area under the plasma concentration-time curve (h·µg/L) of the combination therapy to monotherapy, assessed at steady state, were as follows: total ezetimibe, 1.0264 (0.8765-1.2017) and 0.9359 (0.7847-1.1163); free ezetimibe, 1.5713 (1.2821-1.9257) and 0.9941 (0.8384-1.1788); rosuvastatin, 2.1673 (1.7807-2.6379) and 1.1714 (0.9992-1.3733); telmisartan, 1.0745 (0.8139-1.4186) and 1.1057 (0.8379-1.4591); and amlodipine, 0.9421 (0.8764-1.0126) and 0.9603 (0.8862-1.0405). Both combination therapy and monotherapy were well tolerated by the subjects. Conclusion: The coadministration of ezetimibe/rosuvastatin 10/20 mg and ezetimibe/rosuvastatin 10/20 mg was well tolerated in healthy subjects, and the PK interaction between those two FDCs was not clinically significant.
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Amlodipino , Estudios Cruzados , Combinación de Medicamentos , Ezetimiba , Voluntarios Sanos , Rosuvastatina Cálcica , Telmisartán , Humanos , Telmisartán/administración & dosificación , Telmisartán/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/administración & dosificación , Amlodipino/farmacocinética , Amlodipino/administración & dosificación , Masculino , Ezetimiba/administración & dosificación , Ezetimiba/farmacocinética , Adulto , Adulto Joven , Benzoatos/farmacocinética , Benzoatos/administración & dosificación , Bencimidazoles/farmacocinética , Bencimidazoles/administración & dosificación , Relación Dosis-Respuesta a Droga , Interacciones FarmacológicasRESUMEN
BACKGROUND: The study evaluated the performance of the Mindray N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a healthy population in China, focusing on creating a reference range for future clinical applications adjusted according to different demographics. METHODS: The study measured NT-proBNP in 2277 healthy individuals. We analyzed age and sex-stratified data, performed precision, accuracy, linearitcvy, and detection limit studies, and evaluated method comparison and consistency between Roche and Mindray assays on 724 serum samples. We used Excel 2010, Medcalc, and GraphPad Prism 9. RESULTS: In males, the 97.5th centile NT-proBNP concentration at age < 45, 45 to 54, 55 to 64, 65 to 74 and ⧠75 were 89.4 ng/L, 126 ng/L, 206 ng/L, 386 ng/L and 522 ng/L, respectively. In females, the concentration of NT-proBNP at the same age was 132 ng/L, 229 ng/L, 262 ng/L, 297 ng/L and 807 ng/L, respectively. The repeatability precision coefficient of variation (CV%) for NT-proBNP was between 0.86 and 1.65 in analytical performance. In contrast, the reproducibility precision (CV%) for NT-proBNP was between 1.52 and 3.22, respectively. The study found a bias of accuracy of 3.73% in low-value samples (concentration: 148.69) and 7.31% in high-value samples (concentration: 1939.08). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 125 ng/L were 96.6%, 92.3%, 84.2%, and 98.5%, respectively. In contrast, those of 300 ng/L were 94.0%, 98.2%, 95.7% and 97.5%, respectively. CONCLUSIONS: The Mindray NT-proBNP assay showed increased levels in both males and females with age, with higher levels in women. It performs well and aligns with manufacturer specifications. We recommend adjusting cutoff values based on demographic factors.
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Biomarcadores , Péptido Natriurético Encefálico , Fragmentos de Péptidos , Valor Predictivo de las Pruebas , Humanos , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Biomarcadores/sangre , Reproducibilidad de los Resultados , Adulto , China , Valores de Referencia , Factores Sexuales , Factores de Edad , Voluntarios Sanos , Anciano de 80 o más Años , Adulto Joven , Límite de DetecciónRESUMEN
This phase I thorough QTc, double-blind, randomized, placebo- and positive-controlled, parallel group, multiple-dose study evaluated avacopan's effect on cardiac repolarization using concentration-QTc (C-QTc) as the primary analysis. Avacopan 30 mg b.i.d. (therapeutic dose) was administered orally on days 1 through 7 followed by avacopan 100 mg b.i.d. (supratherapeutic dose) on days 8 through 14 in 29 healthy participants. Moxifloxacin 400 mg and placebo were administered on days 1 and 15 in a nested crossover design for assay sensitivity in separate cohorts to 28 participants. Time-matched plasma concentrations and up to 10 replicate ECGs were obtained on prespecified days at baseline and postdose on days 1, 7, 14, and 15. The mean change from baseline on QTcF for avacopan (-5.5 to 3.5 ms) was similar to placebo (-6.9 to 1.4 ms) across days 1, 7, and 14. The mean effect on ΔΔQTcF (90% CI) was estimated as 1.5 ms (-0.17 to 3.09) and 0.8 ms (-2.41 to 4.05) for 30 and 100 mg avacopan b.i.d. treatments, respectively. Based on the C-QTc analysis, avacopan's effect on ΔΔQTcF >10 ms can be excluded within the observed plasma concentration range of up to ~1220 and ~335 ng/mL for avacopan and active major metabolite, M1, respectively. The estimated population slopes showed a shallow relationship, which was not statistically significant. There was no clinically meaningful effect of avacopan on heart rate or cardiac conduction (PR and QRS intervals). Avacopan appeared to be generally well tolerated in this study population.
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Estudios Cruzados , Relación Dosis-Respuesta a Droga , Electrocardiografía , Voluntarios Sanos , Frecuencia Cardíaca , Humanos , Masculino , Adulto , Femenino , Método Doble Ciego , Adulto Joven , Frecuencia Cardíaca/efectos de los fármacos , Persona de Mediana Edad , Moxifloxacino/administración & dosificación , Moxifloxacino/efectos adversos , Moxifloxacino/farmacocinética , AdolescenteRESUMEN
N-methyl-D-aspartate receptor (NMDAR)-positive allosteric modulators (PAMs) represent a potential therapeutic strategy for cognitive impairment in disorders associated with NMDAR hypofunction, including Huntington's disease (HD) and Alzheimer's disease. Dalzanemdor (SAGE-718) is a novel, investigational NMDAR PAM being evaluated for the potential treatment of cognitive impairment in these disorders. We report first-in-human, phase I, double-blind, dose-finding studies to assess the safety, tolerability, and clinical pharmacology of dalzanemdor. A single-ascending dose study (dalzanemdor 0.35, 0.75, 1.5, or 3.0 mg vs. placebo) was conducted in healthy participants and included food effects. A multiple-ascending dose study (14 days) was conducted in healthy participants (dalzanemdor 0.5 or 1.0 mg vs. placebo) and HD participants (open-label dalzanemdor 1.0 mg) and included exploratory pharmacodynamics on cognitive performance. Dalzanemdor was generally well tolerated with no adverse events leading to discontinuation. Dalzanemdor exhibited pharmacokinetic parameters appropriate for once-daily dosing. Following single and multiple doses in healthy participants, median terminal half-life was 8-118 h, and the median time to reach maximum plasma concentration was 4-7 h. Exposures were dose-proportional after single dose (6-46 ng/mL) and more than dose-proportional after multiple doses (6-41 ng/mL). With multiple dosing, a steady state was achieved after 11 days in healthy participants and 13 days in HD participants. Dalzanemdor exposure decreased slightly with food. In HD participants, results suggest that dalzanemdor may improve cognitive performance on tests of executive function. These results support continued clinical development of dalzanemdor for the potential treatment of cognitive impairment in disorders of NMDAR hypofunction.