The effects of two 8 week programmes of reconditioning in chronic obstructive pulmonary disease (COPD) patients were studied. Forty one subjects (mean+/-SD) 644.5) yrs; forced expiratory volume in ...one second (FEV1) 1.09+/-0.16 L; 40.6+/-6.2% predicted were randomly assigned either to supervised training on a treadmill, 4 days x week(-1) (group S; n=21) or walking 3 or 4 km in 1 h 4 days x week(-1), self-monitored with a pedometer, with weekly visits to encourage adherence (group SM; n=20). Patients were evaluated with the chronic respiratory diseases questionnaire (CRQ) and two exercise tests on a treadmill: incremental (IT) and constant (CT), above lactic threshold or 70% of maximal oxygen uptake (VO2, max) with arterial blood lactate determinations. Estimated mean work rate of training was 69+/-27 W and 25+/-5 W respectively for groups S and SM. Both types of training produced similar changes in the four dimensions of the CRQ. In group S reconditioning yielded significant (p<0.05) increases in VO2, max and increases in duration, with decreased lactate accumulation, ventilation, CO2 output (VCO2), heart rate (HR) and diastolic blood pressure (DBP) at the end of CT. They also adopted a deeper slower pattern of breathing during exercise. The SM group showed significant (p<0.05) increases in duration, lower HR and DBP at the end of CT. Significantly (p<0.05) different effects between S and SM programmes were changes in VO2, max 100+/-101 mL x min(-1) versus 5+/-101 mL x min(-1)), duration of the CT (8.1+/-4.4 min versus 3.9+/-4.7 min), VCO2 (-94+/-153 mL x min(-1) versus 48+/-252 mL x min(-1)), lactate accumulation (-1.3+/-2.2 mmol x L(-1) versus 0+/-1.2 mmol x L(-1) and respiratory rate at the end of CT (4.3+/-3.4 min(-1) versus -1+/-4.2 min(-1)). Supervised, intense training yields physiological improvements in severe chronic obstructive pulmonary disease patients not induced by self-monitored training. The self-monitored, less intense training, increases submaximal exercise endurance, although to a lesser degree.
The pathogenic mechanisms underlying the progression of non-alcoholic fatty liver disease (NAFLD) are not fully understood. In this study, we aimed to assess the relationship between endoplasmic ...reticulum (ER) stress and autophagy in human and mouse hepatocytes during NAFLD. ER stress and autophagy markers were analyzed in livers from patients with biopsy-proven non-alcoholic steatosis (NAS) or non-alcoholic steatohepatitis (NASH) compared with livers from subjects with histologically normal liver, in livers from mice fed with chow diet (CHD) compared with mice fed with high fat diet (HFD) or methionine-choline-deficient (MCD) diet and in primary and Huh7 human hepatocytes loaded with palmitic acid (PA). In NASH patients, significant increases in hepatic messenger RNA levels of markers of ER stress (activating transcription factor 4 (ATF4), glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP)) and autophagy (BCN1) were found compared with NAS patients. Likewise, protein levels of GRP78, CHOP and p62/SQSTM1 (p62) autophagic substrate were significantly elevated in NASH compared with NAS patients. In livers from mice fed with HFD or MCD, ER stress-mediated signaling was parallel to the blockade of the autophagic flux assessed by increases in p62, microtubule-associated protein 2 light chain 3 (LC3-II)/LC3-I ratio and accumulation of autophagosomes compared with CHD fed mice. In Huh7 hepatic cells, treatment with PA for 8 h triggered activation of both unfolding protein response and the autophagic flux. Conversely, prolonged treatment with PA (24 h) induced ER stress and cell death together with a blockade of the autophagic flux. Under these conditions, cotreatment with rapamycin or CHOP silencing ameliorated these effects and decreased apoptosis. Our results demonstrated that the autophagic flux is impaired in the liver from both NAFLD patients and murine models of NAFLD, as well as in lipid-overloaded human hepatocytes, and it could be due to elevated ER stress leading to apoptosis. Consequently, therapies aimed to restore the autophagic flux might attenuate or prevent the progression of NAFLD.
Successful behaviour relies on the appropriate interplay between action and perception. The well-established dorsal and ventral stream theories depicted two distinct functional pathways for the ...processes of action and perception, respectively. In physiological conditions, the two pathways closely cooperate in order to produce successful adaptive behaviour. As the coupling between perception and action exists, this requires an interface that is responsible for a common reading of the two functions. Several studies have proposed different types of perception and action interfaces, suggesting their role in the creation of the shared interaction channel. In the present review, we describe three possible perception and action interfaces: i) the motor code, including common coding approaches, ii) attention, and iii) object affordance; we highlight their potential neural correlates. From this overview, a recurrent neural substrate that underlies all these interface functions appears to be crucial: the parieto-frontal circuit. This network is involved in the mirror mechanism which underlies the perception and action interfaces identified as common coding and motor code theories. The same network is also involved in the spotlight of attention and in the encoding of potential action towards objects; these are manifested in the perception and action interfaces for common attention and object affordance, respectively. Within this framework, most studies were dedicated to the description of the role of the inferior parietal lobule; growing evidence, however, suggests that the superior parietal lobule also plays a crucial role in the interplay between action and perception. The present review proposes a novel model that is inclusive of the superior parietal regions and their relative contribution to the different action and perception interfaces.
In the winter of 1714–1715, a large rotational landslide originated on the northern slope of the Sierra de Aralar (Navarra, Spain), generating an earthflow that slowly descended through the valley ...for a kilometer and a half destroying the village of Inza. An interdisciplinary research recreated the historical process of the event and the geomorphological characterization of this large landslide. The geological analysis and hydrogeological characteristics of the site also identified the determining factors of this historical event. From the analysis that triggered the landslide and how the climate affected events can now be demonstrated from historical records of excess rainfall and the initial start of the process. From the recreated pre-failure topography, the stability of the original slope was studied using a 3D numerical model to identify the factors, causes and mechanism that controlled the development of the landslide.
Inhibition of protein tyrosine phosphatase 1B (PTP1B) has been suggested as an attractive target to improve insulin sensitivity in different cell types. In the present work, we have investigated the ...effect of PTP1B deficiency on the response of human and murine macrophages. Using in vitro and in vivo approaches in mice and silencing PTP1B in human macrophages with specific siRNAs, we have demonstrated that PTP1B deficiency increases the effects of pro-inflammatory stimuli in both human and rodent macrophages at the time that decreases the response to alternative stimulation. Moreover, the absence of PTP1B induces a loss of viability in resting macrophages and mainly after activation through the classic pathway. Analysis of early gene expression in macrophages treated with pro-inflammatory stimuli confirmed this exacerbated inflammatory response in PTP1B-deficient macrophages. Microarray analysis in samples from wild-type and PTP1B-deficient macrophages obtained after 24 h of pro-inflammatory stimulation showed an activation of the p53 pathway, including the excision base repair pathway and the insulin signaling pathway in the absence of PTP1B. In animal models of lipopolysaccharide (LPS) and D-galactosamine challenge as a way to reveal in vivo inflammatory responses, animals lacking PTP1B exhibited a higher rate of death. Moreover, these animals showed an enhanced response to irradiation, in agreement with the data obtained in the microarray analysis. In summary, these results indicate that, although inhibition of PTP1B has potential benefits for the treatment of diabetes, it accentuates pro-inflammatory responses compromising at least macrophage viability.
We propose that several short-duration events observed in past stellar occultations by Chiron were produced by ring material. Some similarities between these events and the characteristics of ...Chariklo’s rings could indicate common mechanisms around centaurs. From a reanalysis of the stellar occultation data in the literature, we determined two possible orientations of the pole of Chiron’s rings, with ecliptic coordinates λ = (352 ± 10)°, β = (37 ± 10)° or λ = (144 ± 10)°, β = (24 ± 10)°. The mean radius of the rings is (324 ± 10) km. One can use the rotational lightcurve amplitude of Chiron at different epochs to distinguish between the two solutions for the pole. Both solutions imply a lower lightcurve amplitude in 2013 than in 1988, when the rotational lightcurve was first determined. We derived Chiron’s rotational lightcurve in 2013 from observations at the 1.23 m CAHA telescope, and indeed its amplitude was smaller than in 1988. We also present a rotational lightcurve in 2000 from images taken at the CASLEO 2.15 m telescope that is consistent with our predictions. Out of the two poles, the λ = (144 ± 10)°, β = (24 ± 10)° solution provides a better match to a compilation of rotational lightcurve amplitudes from the literature and those presented here. We also show that using this preferred pole orientation, Chiron’s long-term brightness variations are compatible with a simple model that incorporates the changing brightness of the rings while the tilt angle with respect to the Earth is changing with time. Also, the variability of the water ice band in Chiron’s spectra as seen in the literature can be explained to a large degree by an icy ring system whose tilt angle changes with time and whose composition includes water ice, analogously to the case of Chariklo. We present several possible formation scenarios for the rings from qualitative points of view and speculate on why rings might be common in centaurs. We also speculate on whether the known bimodal color distribution of the centaurs could be due to centaurs with rings and centaurs without rings.
MicroRNAs (miRNAs), small noncoding RNAs modulating messenger RNA (mRNA) and protein expression, have emerged as key regulatory molecules in chronic liver diseases, whose end stage is hepatic ...fibrosis, a major global health burden. Pharmacological strategies for prevention or treatment of hepatic fibrosis are still limited, what makes it necessary to establish a better understanding of the molecular mechanisms underlying its pathogenesis. In this context, we have recently shown that cyclooxygenase-2 (COX-2) expression in hepatocytes restricts activation of hepatic stellate cells (HSCs), a pivotal event in the initiation and progression of hepatic fibrosis. Here, we evaluated the role of COX-2 in the regulation of a specific set of miRNAs on a mouse model of CCl4 and bile duct ligation (BDL)-induced liver fibrosis. Our results provide evidence that COX-2 represses miR-23a-5p and miR-28-5p expression in HSC. The decrease of miR-23a-5p and miR-28-5p expression promotes protection against fibrosis by decreasing the levels of pro-fibrogenic markers α-SMA and COL1A1 and increasing apoptosis of HSC. Moreover, we demonstrate that serum levels of miR-28-5p are decreased in patients with chronic liver disease. These results suggest a protective effect exerted by COX-2-derived prostanoids in the process of hepatofibrogenesis.
•hCOX-2 Tg mice have attenuated fibrosis by modulating miR-23a and miR-28 in HSCs.•Hepatic PGE2 production downregulates miR-23a and miR-28 in HSCs.•Downregulation of miR-23a and miR-28a decreases activation of HSC.•Decreased proliferation and increased apoptosis of HSC lead to fibrosis resolution.
Abstract
Objectives
Rheumatic and musculoskeletal diseases (RMDs) require a tailored follow-up that can be enhanced by the implementation of innovative tools. The Digireuma study aimed to test the ...feasibility of a hybrid follow-up utilizing an electronic patient reported outcomes (ePROs)-based monitoring strategy in patients with RMDs.
Methods
Adult patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) were recruited for a 6-month bicentric prospective follow-up consisting of face-to-face and digital assessments. Patients were asked to report disease-specific ePROs on a pre-established basis, and could also report flares, medication changes, and recent infections at any time. Four rheumatologists monitored these outcomes and contacted patients for interventions when deemed necessary. Results from face-to-face and digital assessments were described.
Results
Of 56 recruited patients, 47 (84%) submitted any ePROs to the digital platform. Most patients with RA were female (74%, median age of 47 years), while 48% of patients with SpA were female (median age 40.4 years). A total of 3,800 platform visits were completed, with a median of 57 and 29 visits in patients with RA and SpA, respectively. Among 52 reported alerts, 47 (90%) needed contact, of which 36 (77%) were managed remotely. Adherence rates declined throughout the study, with around half of patients dropping out during the 6 months follow-up.
Conclusion
The implementation of a hybrid follow-up in clinical practice is feasible. Digital health solutions can provide granular knowledge of disease evolution and enable more informed clinical decision making, leading to improved patient outcomes. Further research is needed to identify target patient populations and engagement strategies.
The effects of two 8-week programmes of exercise reconditioning on the time constants (tau) of the pulmonary gas exchange, ventilatory and heart rate responses to moderate intensity exercise in ...patients with chronic obstructive pulmonary disease (COPD) were studied. Thirty-five subjects (mean+/-SD 64+/-5 yrs; forced expiratory volume in one second (FEV1) 1.09+/-0.17 L; 41+/-6.2% predicted) were randomly assigned either to supervised (s) training on a treadmill, 4 days x week(-1) (group S; n=21) or self-monitored (SM) walking 3 or 4 km in 1 h 4 days x week(-l) (group SM; n=20). The different levels of supervision resulted in a different estimated intensity of training (35+/-10 W in the SM group and 70+/-22 W in the S group). The kinetics were evaluated with a constant-load exercise test on a cycle-ergometer at a work rate corresponding to 80% the highest oxygen consumption (V'O2) that can be achieved without blood lactic acidosis (V'O2,LAT) or 50% of V'O2,max, if maximum oxygen consumption V'O2,LAT was not found. Mean endurance time at a work rate equivalent to 70% of the pretraining V'O2,max increased by 493+/-281 s in the S group and 254+/-283 s in the SM group (p<0.001). Mean tauV'O2 decreased from 83+/-17 s to 67+/-11 s (p<0.0001) in the S group and from 84+/-12 to 79+/-16 (p=0.04) in the SM group. Mean tau for carbon dioxide output minute ventilation and heart rate were also speeded after training, again more markedly in the S group. In the S group there was a significant correlation between the decrease in tauV'O2 and the increase in endurance time (r=-0.56, SEM=0.21). It is concluded that training speeds the kinetic response of oxygen consumption, carbon dioxide production, minute ventilation and heart rate to moderate exercise and that the effect is greater after supervised, more intense training.
Abstract We report here the performance and first results of the new multiband optical polarimeter DIPOL-1, installed at the Sierra Nevada Observatory 90 cm T90 telescope (SNO, Granada, Spain). ...DIPOL-1 is equipped with a plane parallel calcite plate and λ /2 retarder for modulating the intensity of two perpendicularly polarized beams, and a high readout speed CMOS camera that allows for fast, time-dense coverage. We characterize the performance of this instrument through a series of tests on zero- and high-polarization standard stars. The instrumental polarization in the Nasmyth focus was well determined, with a very stable contribution of 4.0806% ± 0.0014% in the optical R band. For bright high-polarization standards ( m R < 8) we reach precisions <0.02% in polarization degree and 0.°1 in polarization angle for exposures of 2–4 min. The polarization properties of these stars have been constrained, providing more recent results also about possible variability for future studies of some of the most used calibrators. Moreover, we have tested the capability of observing much fainter objects, in particular through blazar observations, where we reach a precision of <0.5%−0.6% and <0.°5 for faint targets ( m R ∼ 16.5) with exposures of ∼1 hr. For brighter targets ( m R ∼ 14.5−15), we can aim for time-dense observations with errors <0.2%−0.4% and <1°−1.°5 in 5–20 min. We have successfully performed a first campaign with DIPOL-1, detecting significant polarized emission of several blazars, with special attention to the highest ever polarization degree measured from blazar 3C 345 at ∼32%.
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