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In the present study, we investigated whether curcumin administration would interfere with the main renal features of l-NAME-induced hypertension model. For this purpose, we conducted both in vitro and in vivo experiments to evaluate renal indicators of inflammation, oxidative stress, and metalloproteinases (MMPs) expression/activity. Hypertension was induced by l-NAME (70 mg/kg/day), and Wistar rats from both control and hypertensive groups were treated with curcumin (50 or 100 mg/kg/day; gavage) or vehicle for 14 days. Blood and kidneys were collected to determine serum creatinine levels, histological alterations, oxidative stress, MMPs expression and activity, and ED1 expression. l-NAME increased blood pressure, but both doses of curcumin treatment reduced these values. l-NAME treatment increased creatinine levels, glomeruli area, Bowman's space, kidney MMP-2 activity, as well as MMP-9 and ED1 expression, and reduced the number of glomeruli. Curcumin treatment prevented the increase in creatinine levels, MMP-2 activity, and reduced MMP-2, MMP-9, ED1, and superoxide levels, as well as increased superoxide dismutase activity and partially prevented glomeruli alterations. Moreover, curcumin directly inhibited MMP-2 activity in vitro. Thus, our main findings demonstrate that curcumin reduced l-NAME-induced hypertension and renal glomerular alterations, inhibited MMP-2 and MMP-9 expression/activity, and reduced oxidative stress and inflammatory processes, which may indirectly impact hypertension-induced renal outcomes.
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Curcumina , Hipertensión , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 9 de la Matriz , NG-Nitroarginina Metil Éster , Animales , Masculino , Ratas , Curcumina/farmacología , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/tratamiento farmacológico , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , NG-Nitroarginina Metil Éster/farmacología , Estrés Oxidativo/efectos de los fármacos , Ratas WistarRESUMEN
This study investigates the efficacy of nebivolol (NBV) in experimental models of toxoplasmosis, focusing on parasite burden reduction and neuronal protection. In the acute model of experimental toxoplasmosis, Swiss mice infected with RH strain tachyzoites received oral NBV chlorhydrate doses of 2 mg/kg/day and 4 mg/kg/day for 8 days. Treatment with NBV significantly reduced parasite burden compared to vehicle and standard drug (PYR) groups. In the chronic model of experimental toxoplasmosis, C57/BL6 mice infected with the ME49 strain received NBV chlorhydrate 41 days post-infection and were evaluated after 10 days of treatment. NBV chlorhydrate effectively reduced cyst number and area, as well as bradyzoite burden compared to controls. Histological analysis demonstrated that NBV chlorhydrate preserved neuronal count, with the 4 mg/kg/day dose yielding counts similar to non-infected mice. Statistical analysis confirmed significant differences compared to control groups. Furthermore, immunohistochemical analysis revealed a significant reduction in iNOS labeling in the brains of mice treated with NBV chlorhydrate, indicating a decrease in nitric oxide production compared to control groups. These findings suggest NBV's potential as a promising candidate for toxoplasmosis treatment, highlighting its ability to reduce parasite burden and protect neuronal integrity. Further research is warranted to elucidate NBV's mechanisms of action and its clinical application in managing toxoplasmosis.
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Encéfalo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Nebivolol , Carga de Parásitos , Toxoplasmosis Animal , Animales , Nebivolol/farmacología , Nebivolol/uso terapéutico , Ratones , Toxoplasmosis Animal/tratamiento farmacológico , Toxoplasmosis Animal/parasitología , Encéfalo/parasitología , Encéfalo/patología , Encéfalo/efectos de los fármacos , Femenino , Neuronas/efectos de los fármacos , Neuronas/parasitología , Etanolaminas/farmacología , Etanolaminas/uso terapéutico , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Antiprotozoarios/administración & dosificación , Benzopiranos/farmacología , Benzopiranos/uso terapéutico , Resultado del Tratamiento , Óxido Nítrico/metabolismo , Toxoplasma/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismoRESUMEN
The impact of diet composition and energy content on schistosomiasis evolution and treatment efficacy is still controversial. This study compared the impact of sucrose-rich diet and intermittent fasting on Schistosoma mansoni infection and praziquantel (PZQ)-based chemotherapy response in mice. BALB/c mice were infected with S. mansoni and followed for 15 weeks. The animals were randomized into nine groups receiving high glycemic load (high-sucrose diet - HSD), low caloric load (standard chow alternate-day fasting - ADF), and standard chow ad libitum (AL). Eight weeks after S. mansoni infection, these groups remained untreated or were treated with PZQ (300 mg/kg/day) for 3 days. Our results indicated that parasite load (S. mansoni eggs and parasite DNA levels), granulomatous inflammation (granulomas number and size), and liver microstructural damage (reduction in hepatocytes number, increase in nucleus-cytoplasm ratio, connective stroma expansion and fibrosis) were increased in ADF-treated animals. These animals also showed decreased eggs retention, granulomatous inflammation and collagen accumulation in the small intestine. Conversely, HSD diet and PZQ treatment attenuated all these parameters and stimulated hepatic regenerative response. PZQ also stimulated fibrosis resolution in HSD-treated mice, effect that was limited ADF-exposed mice. Our findings indicate that dietary glycemic and energy load can modulate schistosomiasis progression and the severity of hepatic and intestinal granulomatous inflammation in untreated and PZQ-treated mice. Thus, lower intestinal eggs retention may potentially be linked to worsening liver disease in ADF, while attenuation of hepatic and intestinal granulomatous inflammation is consistent with reduced parasite load in HSD- and PZQ-treated animals.
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Antihelmínticos , Hepatopatías , Esquistosomiasis mansoni , Esquistosomiasis , Animales , Ratones , Schistosoma mansoni , Antiparasitarios/uso terapéutico , Praziquantel/farmacología , Esquistosomiasis mansoni/tratamiento farmacológico , Esquistosomiasis mansoni/parasitología , Hígado/parasitología , Esquistosomiasis/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Fibrosis , Dieta , Sacarosa/farmacología , Sacarosa/uso terapéutico , Antihelmínticos/uso terapéuticoRESUMEN
Disruption of the brain serotoninergic (5-HT) system during development induces long-lasting changes in molecular profile, cytoarchitecture, and function of neurons, impacting behavioral regulation throughout life. In male and female rats, we investigate the effect of neonatal tryptophan hydroxylase (TPH) inhibition by using para-chlorophenylalanine (pCPA) on the expression of 5-HTergic system components and neuropeptides related to adolescent social play behavior regulation. We observed sex-dependent 5-HT levels decrease after pCPA-treatment in the dorsal raphe nucleus (DRN) at 17 and 35 days. Neonatal pCPA-treatment increased playing, social and locomotory behaviors assessed in adolescent rats of both sexes. The pCPA-treated rats demonstrated decreased Crh (17 days) and increased Trh (35 days) expression in the hypothalamic paraventricular nucleus (PVN). There was sex dimorphism in Htr2c (17 days) and VGF (35 days) in the prefrontal cortex, with the females expressing higher levels of it than males. Our results indicate that neonatal pCPA-treatment results in a long-lasting and sex-dependent DRN 5-HT synthesis changes, decreased Crh, and increased Trh expression in the PVN, resulting in a hyperactivity-like phenotype during adolescence. The present work demonstrates that the impairment of TPH function leads to neurobehavioral disorders related to hyperactivity and impulsivity, such as attention deficit hyperactivity disorder (ADHD).
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Núcleo Hipotalámico Paraventricular , Serotonina , Ratas , Femenino , Masculino , Animales , Fenclonina/farmacología , Núcleo Hipotalámico Paraventricular/metabolismo , Serotonina/metabolismo , Núcleo Dorsal del Rafe/metabolismo , Triptófano Hidroxilasa/metabolismoRESUMEN
Despite current literature pointing to a link between shortened telomeres and aging, chronic diseases, and geriatric syndromes, the precise implications of this connection remain unclear. The aim of this exploratory, cross-sectional, observational study was to investigate the association between the relative telomere length (RTL) of peripheral blood leukocyte subtypes (mononuclear cells and granulocytes) and physical performance using the Short Physical Performance Battery (SPPB) in older adults. A cohort of 95 participants was recruited, which included men and women aged over 60 years (70.48 ± 5.5 years). It was found that mononuclear cell RTL was significantly lower than that of granulocytes (p < 0.0001). Moreover, individuals with good SPPB performance exhibited lower mononuclear cell RTL compared with those with moderate or poor performance. However, no significant differences were observed in granulocyte RTL between different SPPB performance groups. The global SPPB score showed an inverse correlation with mononuclear cell RTL, but this correlation was not present with granulocyte RTL. Similarly, the SPPB sit-to-stand domain correlated with mononuclear cell RTL, but no such correlation was found with granulocyte RTL. Our findings challenge conventional expectations, suggesting that shorter mononuclear cell RTL may be associated with favorable functional capacity. The variations in RTL between mononuclear cells and granulocytes highlight their distinct biological roles and turnover rates. A history of immune responses may influence mononuclear cell RTL dynamics, while telomerase activity may protect granulocyte RTL from significant shortening. The unexpected associations observed in mononuclear cell RTL emphasize the complex interplay between immune responses, cellular aging, and functional capacity in older adults.
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Envejecimiento , Leucocitos , Masculino , Humanos , Femenino , Anciano , Persona de Mediana Edad , Estudios Transversales , Acortamiento del Telómero , Telómero , Rendimiento Físico FuncionalRESUMEN
Background: The acute clinical repercussions of SARS-CoV-2 infection have been widely studied. However, the possible late repercussions of long COVID have not yet been well defined in the literature. Objectives: To identify the presence of pain and musculoskeletal disability in patients with Long COVID and also to identify predictive factors for pain intensity in this population. Methods: In this cross-sectional and retrospective observational study individuals with Long COVID symptoms were included. It was collected musculoskeletal disability measures, data from patient-related outcome measures and variables from a COVID-19 outpatient service database. Associations and sub-group analyses were performed considering the variables pain, disability and hospitalization. Linear regression was performed to identify predictive factors for pain intensity in Long COVID patients. Results: We evaluated 195 patients and most of them (57%) presented musculoskeletal pain in one area of the body. Pain sub-group presented worse disability indices and worse clinical course during hospitalization. Hospitalized patients presented worse disability indices comparing to non-hospitalized. Significant correlations were found between pain and days of non-invasive oxygen support (r = 0.21; p = 0.003); days in intensive care unit (r = 0.22; p = 0.002) and days in invasive mechanical ventilation (r = 0.35; p = 0.001). Hospitalized individuals showed a higher chance of presenting late musculoskeletal pain (OR = 1.42: 95%CI 1.09-2.04). Days in intensive care unit (ß = 0,234: P = 0,001) and days in invasive mechanical ventilation (ß = 0.764: P = 0.001) were predictors of pain intensity [F(2,192) = 18.559; R2 = 0.231; p = 0.001]. Conclusion: Individuals with Long COVID presented musculoskeletal pain and disability. Hospitalized patients showed a greater chance of having musculoskeletal pain. Days in intensive care unit and days in invasive mechanical ventilation were predictors of late musculoskeletal pain intensity.
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Although it has been previously demonstrated that oxytocin (OXT) receptor stimulation can control skeletal muscle mass in vivo, the intracellular mechanisms that mediate this effect are still poorly understood. Thus, rat oxidative skeletal muscles were isolated and incubated with OXT or WAY-267,464, a non-peptide selective OXT receptor (OXTR) agonist, in the presence or absence of atosiban (ATB), an OXTR antagonist, and overall proteolysis was evaluated. The results indicated that both OXT and WAY-267,464 suppressed muscle proteolysis, and this effect was blocked by the addition of ATB. Furthermore, the WAY-induced anti-catabolic action on protein metabolism did not involve the coupling between OXTR and Gαi since it was insensitive to pertussis toxin (PTX). The decrease in overall proteolysis induced by WAY was probably due to the inhibition of the autophagic/lysosomal system, as estimated by the decrease in LC3 (an autophagic/lysosomal marker), and was accompanied by an increase in the content of Ca2+-dependent protein kinase (PKC)-phosphorylated substrates, pSer473-Akt, and pSer256-FoxO1. Most of these effects were blocked by the inhibition of inositol triphosphate receptors (IP3R), which mediate Ca2+ release from the sarcoplasmic reticulum to the cytoplasm, and triciribine, an Akt inhibitor. Taken together, these findings indicate that the stimulation of OXTR directly induces skeletal muscle protein-sparing effects through a Gαq/IP3R/Ca2+-dependent pathway and crosstalk with Akt/FoxO1 signaling, which consequently decreases the expression of genes related to atrophy, such as LC3, as well as muscle proteolysis.
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Músculo Esquelético , Proteolisis , Proteínas Proto-Oncogénicas c-akt , Receptores de Oxitocina , Animales , Ratas , Músculo Esquelético/metabolismo , Oxitocina/farmacología , Oxitocina/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Oxitocina/genética , Transducción de SeñalRESUMEN
Home exercises (HE) with minimal resources seem to be useful in individuals with COPD. The objective was to evaluate the effects of HE, on activities of daily living (ADL), dyspnea, on the health status(CAT) and quality of life (HRQoL) of individuals with COPD GOLD II to IV. Quasi-experimental study of the effects of HE, for 2 months, 3 times a week. Individuals with COPD(n = 45) were recruited, 37 started the protocol(9 did not complete it). 28 individuals (mean age 62.04 ± 5.8 years, FEV1: 44.7 ± 2.25%, FEV1/FVC 59.8 ± 6.9%) were evaluated before and after training. We observed improvements in the ADL-Glittre (4.9 ± 1.4 vs 3.9 ± 1.1 min; mean difference: -0.9 ± 0.2 min [95%CI: -1.3 to -0.2]; p = 0.008), as well as the mMRC score(2.8 ± 1.1 vs 2.07 ± 0.81; mean difference: 0.7 ± 0.3 [95%CI: -1.20.18 to -0.2]; p = 0.009), and in the CAT (25.6 ± 4.8 vs 18.9 ± 3.1; mean difference: -6.6 ± 3.4 [95%CI: -10.6 to -1.6]; p = 0.042). Analyzing the mean change before and after the intervention, a weak correlation was observed between ADL-Glittre and mMRC (r = 0.35; [95% CI 0.09; 0.56]; p = 0.009); moderate between ADL-Glittre and CAT (r = 0.52; [95% CI 0.30; 0.69]; p < 0.001) and between ADL-Glittre and SGRQ (r = 0.50; [95% CI 0 .27; 0.67]; p < 0.001). Individuals with COPD can benefit from HE performed autonomously and with minimal resources, as this proposal improves functional capacity for ADL, health perception and dyspnea.
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Actividades Cotidianas , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Persona de Mediana Edad , Anciano , Prueba de Esfuerzo , Calidad de Vida , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/terapia , Estado de Salud , Disnea/etiología , Disnea/terapia , Terapia por EjercicioRESUMEN
The purpose of this study was to characterize the role of ß1-AR signaling and its cross-talk between cardiac renin-angiotensin system and thyroid-hormone-induced cardiac hypertrophy. T3 was administered at 0.5 mg·kg-1·day-1 for 10 days in ß1-KOT3 and WTT3 groups, while control groups received vehicle alone. Echocardiography and myocardial histology was performed; cardiac and serum ANGI/ANGII and ANP and cardiac levels of p-PKA, p-ERK1/2, p-p38-MAPK, p-AKT, p-4EBP1, and ACE were measured. WTT3 showed decreased IVSTd and increased LVEDD versus WTsal (p < 0.05). ß1-KOT3 exhibited lower LVEDD and higher relative IVSTd versus ß1-KOsal, the lowest levels of ejection fraction, and the highest levels of cardiomyocyte diameter (p < 0.05). Cardiac ANP levels decreased in WTT3 versus ß1-KOT3 (p < 0.05). Cardiac ACE expression was increased in T3-treated groups (p < 0.05). Phosphorylated-p38 MAPK levels were higher in WTT3 versus WTsal or ß1-KOT3, p-4EBP1 was elevated in ß1-KO animals, and p-ERK1/2 was up-regulated in ß1-KOT3. These findings suggest that ß1-AR signaling is crucial for TiCH.
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Cardiomiopatía Restrictiva , Ratones , Animales , Cardiomiopatía Restrictiva/metabolismo , Cardiomiopatía Restrictiva/patología , Ratones Noqueados , Miocardio/metabolismo , Hormonas Tiroideas , Receptores Adrenérgicos/metabolismo , Angiotensina II/farmacologíaRESUMEN
In addition to being recognised for involvement in cardiovascular control and hydromineral balance, the renin-angiotensin system (RAS) has also been associated with the neuroendocrine control of energy balance. One of the main brain sites for angiotensin II (ANG II)/type 1 receptor (AT1 R) signalling is the subfornical organ (SFO), a circumventricular organ related to the control of autonomic functions, motivated behaviours and energy metabolism. Thus, we hypothesised that circulating ANG II may act on the SFO AT1 R receptors to integrate metabolic and hydromineral balance. We evaluated whether food deprivation can modulate systemic RAS activity and Agrt1a brain expression, and if ANG II/AT1 R signalling influences the hypothalamic expression of mRNAs encoding neuropeptides and food and water ingestion in fed and fasted Wistar rats. We found a significant increase in both ANG I and ANG II plasma levels after 24 and 48 h of fasting. Expression of Agrt1a mRNA in the SFO and paraventricular nucleus (PVN) also increased after food deprivation for 48 h. Treatment of fasted rats with low doses of losartan in drinking water attenuated the decrease in glycemia and meal-associated water intake without changing the expression in PVN or arcuate nucleus of mRNAs encoding selected neuropeptides related to energy homeostasis control. These findings point to a possible role of peripheral ANG II/SFO-AT1 R signalling in the control of refeeding-induced thirst. On the other hand, intracerebroventricular losartan treatment decreased food and water intake over dark time in fed but not in fasted rats.
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Ayuno , Órgano Subfornical , Animales , Masculino , Ratas , Angiotensina II/farmacología , Encéfalo/metabolismo , Ayuno/metabolismo , Losartán/farmacología , Núcleo Hipotalámico Paraventricular/metabolismo , Ratas Wistar , Receptor de Angiotensina Tipo 1/metabolismo , Órgano Subfornical/metabolismoRESUMEN
OBJECTIVES: To evaluate the factors associated with mortality in mechanically ventilated patients with acute respiratory distress syndrome due to COVID-19. METHODS: This was a retrospective, multicenter cohort study that included 425 mechanically ventilated adult patients with COVID-19 admitted to 4 intensive care units. Clinical data comprising the SOFA score, laboratory data and mechanical characteristics of the respiratory system were collected in a standardized way immediately after the start of invasive mechanical ventilation. The risk factors for death were analyzed using Cox regression to estimate the risk ratios and their respective 95%CIs. RESULTS: Body mass index (RR 1.17; 95%CI 1.11 - 1.20; p < 0.001), SOFA score (RR 1.39; 95%CI 1.31 - 1.49; p < 0.001) and driving pressure (RR 1.24; 95%CI 1.21 - 1.29; p < 0.001) were considered independent factors associated with mortality in mechanically ventilated patients with acute respiratory distress syndrome due to COVID-19. Respiratory system compliance (RR 0.92; 95%CI 0.90 - 0.93; p < 0.001) was associated with lower mortality. The comparative analysis of the survival curves indicated that patients with respiratory system compliance (< 30mL/cmH2O), a higher SOFA score (> 5 points) and higher driving pressure (> 14cmH2O) were more significantly associated with the outcome of death at 28 days and 60 days. CONCLUSION: Patients with a body mass index > 32kg/m2, respiratory system compliance < 30mL/cmH2O, driving pressure > 14cmH2O and SOFA score > 5.8 immediately after the initiation of invasive ventilatory support had worse outcomes, and independent risk factors were associated with higher mortality in this population.
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COVID-19 , Síndrome de Dificultad Respiratoria , Adulto , Humanos , Estudios de Cohortes , Respiración Artificial , Estudios Retrospectivos , Síndrome de Dificultad Respiratoria/terapiaRESUMEN
This study explored the association of multiple risk factors with musculoskeletal function in adults hospitalized for acute coronary syndrome. Sixty-nine inpatients (55 ± 6 years; 67% male) admitted to the cardiology ward within <12 h were assessed regarding stress, smoking, alcoholism, hypertension, diabetes mellitus, and obesity. The musculoskeletal function was assessed by predicted values of handgrip strength of the dominant hand (HGS-D%) and maximal inspiratory and expiratory pressures (MIP% and MEP%, respectively). After adjustment by age and sex, drinking habits showed the strongest linear association with the total number of cardiovascular disease risk factors [standardized ß, p-value] (ß = 0.110, p < 0.001), followed by smoking load (ß = 0.028, p = 0.009). Associations were also observed for HGS-D% with mean blood pressure (ß = 0.019 [0.001; 0.037], p = 0.048); MIP% with mean blood pressure (ß = 0.025 [0.006; 0.043], p = 0.013); and MEP% with drinking habits (ß = 0.009 [0.002; 0.016], p = 0.013) and body mass index (ß = 0.008 [0.000; 0.015], p = 0.035). Peripheral and respiratory muscle strength must be interpreted in the context of its association with cardiovascular disease risk factors in adults hospitalized for acute coronary syndrome.
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BACKGROUND AND OBJECTIVES: Although peak oxygen uptake (VO2peak ) is one of the most important measures in clinical practice, the high cost and time consumption have led to the search for simpler devices and the development of the estimating cardiopulmonary fitness (eCPF) equation. Since the lungs are one of the sites most affected by rheumatoid arthritis (RA), this study aimed to create a predictive equation for VO2peak obtained by simple sampling technology in women with RA-associated interstitial lung disease (RA-ILD). METHODS: This cross-sectional study evaluated 47 women with RA-ILD. The participants underwent the following evaluations: computed tomography (CT); evaluation of disease activity through the Clinical Disease Activity Index (CDAI); measurement of physical function using the Health Assessment Questionnaire disability index (HAQ-DI); pulmonary function testing, including spirometry, diffusing capacity for carbon monoxide (DlCO ), nitrogen single-breath washout (N2 SBW) test, and impulse oscillometry; and cardiopulmonary exercise testing (CPET) using FitMate™. RESULTS: VO2peak was correlated with age (r = -0.550, p < 0.0001), rheumatoid factor (r = -0.443, p = 0.002), anti-cyclic citrullinated peptide antibodies (r = -0.410, p = 0.004), CDAI (r = -0.462, p = 0.001), HAD-DI (r = -0.486, p = 0.0005), forced vital capacity (r = 0.491, p = 0.0004), DlCO (r = 0.621, p < 0.0001), phase III slope of N2 SBW (r = -0.647, p < 0.0001), resonance frequency (Fres , r = -0.717, p < 0.0001), integrated low-frequency reactance (r = -0.535, p = 0.0001), and the inhomogeneity of respiratory system resistance between 4 and 20 Hz (r = -0.631, p < 0.0001). In the CT examination, patients with extensive ILD had significantly lower VO2peak than patients with limited ILD (p < 0.0001). In the stepwise forward regression analysis, Fres , DlCO and age explained 61% of the VO2peak variability. CONCLUSIONS: As assessed by CPET, women with RA-ILD show reduced cardiopulmonary fitness, which can be explained at least in part by the presence of small airway disease, deterioration of pulmonary gas exchange, and advanced age. These associations of pulmonary variables with eCPF may be clinically important and support the use of the eCPF equation to improve patient outcomes.
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BACKGROUND: The profile of changes in airway driving pressure (dPaw) induced by positive-end expiratory pressure (PEEP) might aid for individualized protective ventilation. Our aim was to describe the dPaw versus PEEP curves behavior in ARDS from COVID-19 patients. METHODS: Patients admitted in three hospitals were ventilated with fraction of inspired oxygen (FiO2) and PEEP initially adjusted by oxygenation-based table. Thereafter, PEEP was reduced from 20 until 6 cmH2O while dPaw was stepwise recorded and the lowest PEEP that minimized dPaw (PEEPmin_dPaw) was assessed. Each dPaw vs PEEP curve was classified as J-shaped, inverted-J-shaped, or U-shaped according to the difference between the minimum dPaw and the dPaw at the lowest and highest PEEP. In one hospital, hyperdistention and collapse at each PEEP were assessed by electrical impedance tomography (EIT). RESULTS: 184 patients (41 including EIT) were studied. 126 patients (68%) exhibited a J-shaped dPaw vs PEEP profile (PEEPmin_dPaw of 7.5 ± 1.9 cmH2O). 40 patients (22%) presented a U (PEEPmin_dPaw of 12.2 ± 2.6 cmH2O) and 18 (10%) an inverted-J profile (PEEPmin_dPaw of 14,6 ± 2.3 cmH2O). Patients with inverted-J profiles had significant higher body mass index (BMI) and lower baseline partial pressure of arterial oxygen/FiO2 ratio. PEEPmin_dPaw was associated with lower fractions of both alveolar collapse and hyperinflation. CONCLUSIONS: A PEEP adjustment procedure based on PEEP-induced changes in dPaw is feasible and may aid in individualized PEEP for protective ventilation. The PEEP required to minimize driving pressure was influenced by BMI and was low in the majority of patients.
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COVID-19 , Síndrome de Dificultad Respiratoria , Humanos , Respiración Artificial , COVID-19/terapia , Respiración con Presión Positiva/métodos , Síndrome de Dificultad Respiratoria/terapia , Oxígeno/uso terapéuticoRESUMEN
Introduction: Vasopressin (AVP) and oxytocin (OXT) are neuropeptides produced by magnocellular neurons (MCNs) of the hypothalamus and secreted through neurohypophysis to defend mammals against dehydration. It was recently demonstrated that MCNs also project to limbic structures, modulating several behavioral responses. Methods and Results: We found that 24 h of water deprivation (WD) or salt loading (SL) did not change exploration or anxiety-like behaviors in the elevated plus maze (EPM) test. However, rats deprived of water for 48 h showed reduced exploration of open field and the closed arms of EPM, indicating hypoactivity during night time. We evaluated mRNA expression of glutamate decarboxylase 1 (Gad1), vesicular glutamate transporter 2 (Slc17a6), AVP (Avpr1a) and OXT (Oxtr) receptors in the lateral habenula (LHb), basolateral (BLA) and central (CeA) amygdala after 48 h of WD or SL. WD, but not SL, increased Oxtr mRNA expression in the CeA. Bilateral pharmacological inhibition of OXTR function in the CeA with the OXTR antagonist L-371,257 was performed to evaluate its possible role in regulating the EPM exploration or water intake induced by WD. The blockade of OXTR in the CeA did not reverse the hypoactivity response in the EPM, nor did it change water intake induced in 48-h water-deprived rats. Discussion: We found that WD modulates exploratory activity in rats, but this response is not mediated by oxytocin receptor signaling to the CeA, despite the upregulated Oxtr mRNA expression in that structure after WD for 48 h.
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Núcleo Amigdalino Central , Ratas , Animales , Núcleo Amigdalino Central/metabolismo , Oxitocina/metabolismo , Receptores de Oxitocina/metabolismo , Deshidratación , Privación de Agua , Agua , ARN Mensajero , Mamíferos/metabolismoRESUMEN
ABSTRACT Objectives: To evaluate the factors associated with mortality in mechanically ventilated patients with acute respiratory distress syndrome due to COVID-19. Methods: This was a retrospective, multicenter cohort study that included 425 mechanically ventilated adult patients with COVID-19 admitted to 4 intensive care units. Clinical data comprising the SOFA score, laboratory data and mechanical characteristics of the respiratory system were collected in a standardized way immediately after the start of invasive mechanical ventilation. The risk factors for death were analyzed using Cox regression to estimate the risk ratios and their respective 95%CIs. Results: Body mass index (RR 1.17; 95%CI 1.11 - 1.20; p < 0.001), SOFA score (RR 1.39; 95%CI 1.31 - 1.49; p < 0.001) and driving pressure (RR 1.24; 95%CI 1.21 - 1.29; p < 0.001) were considered independent factors associated with mortality in mechanically ventilated patients with acute respiratory distress syndrome due to COVID-19. Respiratory system compliance (RR 0.92; 95%CI 0.90 - 0.93; p < 0.001) was associated with lower mortality. The comparative analysis of the survival curves indicated that patients with respiratory system compliance (< 30mL/cmH2O), a higher SOFA score (> 5 points) and higher driving pressure (> 14cmH2O) were more significantly associated with the outcome of death at 28 days and 60 days. Conclusion: Patients with a body mass index > 32kg/m2, respiratory system compliance < 30mL/cmH2O, driving pressure > 14cmH2O and SOFA score > 5.8 immediately after the initiation of invasive ventilatory support had worse outcomes, and independent risk factors were associated with higher mortality in this population.
RESUMO Objetivos: Avaliar os fatores associados à mortalidade em pacientes ventilados mecanicamente com síndrome o desconforto respiratório agudo por evolução da COVID-19. Métodos: Estudo de coorte retrospectiva, multicêntrica, que incluiu 425 pacientes adultos com COVID-19, ventilados mecanicamente, internados em 4 unidades de terapia intensiva. Foram coletados dados clínicos que compõem o escore SOFA, dados laboratoriais e características mecânicas do sistema respiratório, de forma padronizada, imediatamente após o início da ventilação mecânica invasiva. Os fatores de risco para óbito foram analisados por meio da regressão de Cox, para estimar as razões de risco, e seus respectivos IC95%. Resultados: Índice de massa corporal (RR de 1,17; IC95% 1,11 - 1,20; p < 0,001), escore SOFA (RR de 1,39; IC95% 1,31 - 1,49; p < 0,001) e driving pressure (RR de 1,24; IC95% 1,21 - 1,29; p < 0,001) foram considerados fatores independentes associados à mortalidade em pacientes ventilados mecanicamente com síndrome do desconforto respiratório agudo por COVID-19. Já a complacência do sistema respiratório (RR de 0,92; IC95% 0,90 - 0,93; p < 0,001) foi associada à menor mortalidade. A análise comparativa das curvas de sobrevida demonstra que pacientes com complacência do sistema respiratório (< 30mL/cmH2O), maior SOFA escore (> 5 pontos) e maior driving pressure (> 14cmH2O) apresentaram maior associação ao desfecho morte em 28 dias e 60 dias. Conclusão: Pacientes com índice de massa corporal > 32kg/m2, complacência do sistema respiratório < 30mL/cmH2O, driving pressure > 14cmH2O e SOFA escore > 5,8, imediatamente após o início da assistência ventilatória invasiva, apresentam piores desfechos no segmento, sendo fatores de risco independentes associados à maior mortalidade nessa população.
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Schistosoma mansoni-induced granulomas result in severe damage to the host's liver, as well as neurological and metabolic disorders. We evaluated the biochemical and behavioral changes during schistosomiasis under three diet protocols: ad libitum (AL), alternate-day fasting (ADF) and a high-sucrose/caloric diet (HSD). Healthy male BALB/c mice were divided into noninfected, matched infected and infected/treated [praziquantel (PZQ)] groups. Caloric intake and energy efficiency coefficients associated with diets were measured. Behavioral (exploratory and locomotor) and biochemical (glucose, triglycerides, total cholesterol, AST, ALT, ALP, and γ-GT) tests and histological analysis were performed. Fifteen weeks postinfection, HSD and PZQ promoted weight gain, with higher caloric consumption than ADF (p < 0.05), reflecting serum glucose levels and lipid profiles. HSD and PZQ prevented liver dysfunction (AST and ALT) and significantly prevented increases in granuloma area (p < 0.05). HSD and PZQ also significantly improved mouse physical performance in exploratory and locomotor behavior (p < 0.05), reversing the impaired motivation caused by infection. These findings showed that ADF worsened the course of S. mansoni infection, while HSD and PZQ, even with synergistic effects, prevented and/or attenuated biochemical and behavioral impairment from infection.
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Antihelmínticos , Esquistosomiasis mansoni , Animales , Antihelmínticos/farmacología , Ayuno , Glucosa , Granuloma/patología , Hígado/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Praziquantel/farmacología , Praziquantel/uso terapéutico , Schistosoma mansoni , Esquistosomiasis mansoni/complicaciones , Sacarosa/farmacología , Sacarosa/uso terapéuticoRESUMEN
Background and Objectives: To estimate the association between admission functional outcomes and exposure to physiotherapy interventions with mortality rate in intensive care unit (ICU) inpatients with cardiovascular diseases and new coronavirus disease (COVID-19). Materials and Methods: Retrospective cohort including 100 ICU inpatients (mean (standard deviation), age 75 (16) years) split into COVID-19+ or COVID-19−. The association of in-ICU death with admission functional outcomes and physiotherapy interventions was investigated using univariable and multivariable regression models. Results: In total, 42 (42%) patients tested positive for COVID-19. In-ICU mortality rate was 37%, being higher for the COVID-19+ group (odds ratio, OR (95% CI): 3.15 (1.37−7.47), p = 0.008). In-ICU death was associated with lower admission ICU Mobility Scale score (0.81 (0.71−0.91), p = 0.001). Restricted mobility (24.90 (6.77−161.94), p < 0.001) and passive kinesiotherapy (30.67 (9.49−139.52), p < 0.001) were associated with in-ICU death, whereas active kinesiotherapy (0.13 (0.05−0.32), p < 0.001), standing (0.12 (0.05−0.30), p < 0.001), or walking (0.10 (0.03−0.27), p < 0.001) were associated with in-ICU discharge. Conclusions: In-ICU mortality was higher for inpatients with cardiovascular diseases who had COVID-19+, were exposed to invasive mechanical ventilation, or presented with low admission mobility scores. Restricted mobility or passive kinesiotherapy were associated with in-ICU death, whereas active mobilizations (kinesiotherapy, standing, or walking) were associated with in-ICU discharge in this population.
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COVID-19 , Enfermedades Cardiovasculares , Anciano , Hospitalización , Humanos , Pacientes Internos , Unidades de Cuidados Intensivos , Modalidades de Fisioterapia , Estudios Retrospectivos , SARS-CoV-2RESUMEN
Serotonin exerts a significant role in the mammalian central nervous system embryogenesis and brain ontogeny. Therefore, we investigate the effect of neonatal treatment of d-fenfluramine (d-FEN), a serotonin (5-HT) releaser, on the behavioral expression of adult male Swiss mice. For this purpose, we divided pregnant female Swiss mice into two groups (n = 6 each and ~35 g). Their offspring were treated with d-FEN (3 mg/kg, s.c.) from postnatal days (PND) 5 to 20. At PND 21, one male puppy of each litter was euthanized; the midbrain and the hippocampus were dissected for RNA analysis. At PND 70, the male offspring underwent a behavioral assessment in the open field, elevated plus-maze, light-dark box, tail suspension, and rotarod test. The programmed animals had a decrease in 5HT1a, serotonin transporter (SERT), and brain-derived neurotrophic factor (BDNF) expression in the mesencephalic raphe region. Alternatively, there was a reduction only in the tryptophan hydroxylase (TPH2) and BDNF expression in the hippocampus. In the light-dark box test, offspring of the treated group had higher latency to light and less time on the light side than the control. Also, it was observed less time of immobility in the tail suspension test. We also observed low motor skill learning in the rotarod test. These findings suggest that programming with d-FEN during the neonatal period alters a mesencephalic and hippocampal serotonergic system, promoting anxiety, antidepressant behavior, low coordination, and motor learning in adults.