RESUMEN
Chronic obstructive pulmonary disease (COPD) is a major, incurable respiratory condition that is primarily caused by cigarette smoking (CS). Neurocognitive disorders including cognitive dysfunction, anxiety and depression are highly prevalent in people with COPD. It is understood that increased lung inflammation and oxidative stress from CS exposure may 'spill over' into the systemic circulation to promote the onset of these extra-pulmonary comorbidities, and thus impacts the quality of life of people with COPD. The precise role of the 'spill-over' of inflammation and oxidative stress in the onset of COPD-related neurocognitive disorders are unclear. The present study investigated the impact of chronic CS exposure on anxiety-like behaviors and social recognition memory, with a particular focus on the role of the 'spill-over' of inflammation and oxidative stress from the lungs. Adult male BALB/c mice were exposed to either room air (sham) or CS (9 cigarettes per day, 5 days a week) for 24 weeks and were either daily co-administered with the NOX2 inhibitor, apocynin (5 mg/kg, in 0.01 % DMSO diluted in saline, i.p.) or vehicle (0.01 % DMSO in saline) one hour before the initial CS exposure of the day. After 23 weeks, mice underwent behavioral testing and physiological diurnal rhythms were assessed by monitoring diurnal regulation profiles. Lungs were collected and assessed for hallmark features of COPD. Consistent with its anti-inflammatory and oxidative stress properties, apocynin treatment partially lessened lung inflammation and lung function decline in CS mice. CS-exposed mice displayed marked anxiety-like behavior and impairments in social recognition memory compared to sham mice, which was prevented by apocynin treatment. Apocynin was unable to restore the decreased Bmal1-positive cells, key in cells in diurnal regulation, in the suprachiasmatic nucleus of the hypothalamus to that of sham levels. CS-exposed mice treated with apocynin was associated with a restoration of microglial area per cell and basal serum corticosterone. This data suggests that we were able to model the CS-induced social recognition memory impairments seen in humans with COPD. The preventative effects of apocynin on memory impairments may be via a microglial dependent mechanism.
Asunto(s)
Fumar Cigarrillos , Neumonía , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Adulto , Masculino , Ratones , Animales , Fumar Cigarrillos/efectos adversos , Microglía , Dimetilsulfóxido/farmacología , Calidad de Vida , Pulmón , Neumonía/complicaciones , Núcleo Supraquiasmático , Hipotálamo , Inflamación/complicaciones , Ratones Endogámicos C57BLRESUMEN
INTRODUCTION: There is a lack of studies evaluating mindfulness-based interventions for children with attention-deficit hyperactivity disorder (ADHD) compared with an evidence-based control. This randomized controlled trial (RCT) evaluated the effects of mindfulness for youth (MYmind) in improving children's attention, behavior, and parent-related outcomes versus cognitive behavioral therapy (CBT). METHODS: A total of 138 families of children with ADHD aged 8-12 years were recruited from the community with 69 randomized to MYmind and 69 to CBT. Participants were assessed at baseline, immediately after intervention, at 3 months and 6 months. The primary outcome was the attention score of the Sky Search subtest of the Test of Everyday Attention for Children (TEA-Ch). Secondary outcomes were child behavior and parent-related assessments. Linear mixed models were used to assess the efficacy of MYmind compared with CBT. RESULTS: Both MYmind and CBT significantly improved children's attention score at 6 months (MYmind: ß = 1.48, p = 0.013, Cohen's d = 0.32; CBT: ß = 1.46, p = 0.008, d = 0.27). There were significant within-group improvements in most secondary outcomes. No significant difference was shown for both primary or secondary outcomes between the two arms at any time point. CONCLUSIONS: Both MYmind and CBT appeared to improve children's attention and behavior outcomes, although no difference was found between these two interventions. This is the largest RCT so far comparing MYmind and CBT although there was loss of follow-up assessments during the pandemic. Further RCTs adopting a non-inferiority design are needed to validate the results.
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Trastorno por Déficit de Atención con Hiperactividad , Terapia Cognitivo-Conductual , Atención Plena , Problema de Conducta , Niño , Humanos , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/terapia , Trastorno por Déficit de Atención con Hiperactividad/psicología , Atención Plena/métodos , Terapia Cognitivo-Conductual/métodos , Padres/psicologíaRESUMEN
BACKGROUND: Cigarette smoking (CS) is the leading cause of chronic obstructive pulmonary disease (COPD). The "spill-over" of pulmonary inflammation into the systemic circulation may damage the brain, leading to cognitive dysfunction. Cessation of CS can improve pulmonary and neurocognitive outcomes, however, its benefit on the neuroinflammatory profile remains uncertain. Here, we investigate how CS exposure impairs neurocognition and whether this can be reversed with CS cessation or an antioxidant treatment. METHODS: Male BALB/c mice were exposed to CS (9 cigarettes/day for 8 weeks) followed by 4 weeks of CS cessation. Another cohort of CS-exposed mice were co-administrated with a glutathione peroxidase mimetic, ebselen (10 mg/kg) or vehicle (5% CM-cellulose). We assessed pulmonary inflammation, spatial and working memory, and the hippocampal microglial, oxidative and synaptic profiles. RESULTS: CS exposure increased lung inflammation which was reduced following CS cessation. CS caused spatial and working memory impairments which were attributed to hippocampal microglial activation and suppression of synaptophysin. CS cessation did not improve memory deficits or alter microglial activation. Ebselen completely prevented the CS-induced working and spatial memory impairments, which was associated with restored synaptophysin expression without altering microglial activation. CONCLUSION: We were able to model the CS-induced memory impairment and microglial activation seen in human COPD. The preventative effects of ebselen on memory impairment is likely to be dependent on a preserved synaptogenic profile. Cessation alone also appears to be insufficient in correcting the memory impairment, suggesting the importance of incorporating antioxidant therapy to help maximising the benefit of cessation.
Asunto(s)
Fumar Cigarrillos , Disfunción Cognitiva , Animales , Fumar Cigarrillos/efectos adversos , Disfunción Cognitiva/etiología , Disfunción Cognitiva/prevención & control , Hipocampo , Humanos , Isoindoles , Pulmón , Masculino , Ratones , Ratones Endogámicos BALB C , Compuestos de Organoselenio , SinaptofisinaRESUMEN
People with chronic obstructive pulmonary disease (COPD) are susceptible to respiratory infections which exacerbate pulmonary and/or cardiovascular complications, increasing their likelihood of death. The mechanisms driving these complications remain unknown but increased oxidative stress has been implicated. Here we investigated whether influenza A virus (IAV) infection, following chronic cigarette smoke (CS) exposure, worsens vascular function and if so, whether the antioxidant ebselen alleviates this vascular dysfunction. Male BALB/c mice were exposed to either room air or CS for 8 weeks followed by inoculation with IAV (Mem71, 1 × 104.5 pfu). Mice were treated with ebselen (10 mg/kg) or vehicle (5% w/v CM-cellulose in water) daily. Mice were culled 3- and 10-days post-infection, and their lungs lavaged to assess inflammation. The thoracic aorta was excised to investigate endothelial and smooth muscle dilator responses, expression of key vasodilatory and oxidative stress modulators, infiltrating immune cells and vascular remodelling. CS increased lung inflammation and caused significant vascular endothelial dysfunction, which was worsened by IAV infection. CS-driven increases in vascular oxidative stress, aortic wall remodelling and suppression of endothelial nitric oxide synthase (eNOS) were not affected by IAV infection. CS and IAV infection significantly enhanced T cell recruitment into the aortic wall. Ebselen abolished the exaggerated lung inflammation, vascular dysfunction and increased T cell infiltration in CS and IAV-infected mice. Our findings showed that ebselen treatment abolished vascular dysfunction in IAV-induced exacerbations of CS-induced lung inflammation indicating it may have potential for the treatment of cardiovascular comorbidities seen in acute exacerbations of COPD (AECOPD).
Asunto(s)
Fumar Cigarrillos , Virus de la Influenza A , Gripe Humana , Neumonía , Enfermedad Pulmonar Obstructiva Crónica , Animales , Azoles/farmacología , Fumar Cigarrillos/efectos adversos , Humanos , Gripe Humana/complicaciones , Isoindoles , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Compuestos de Organoselenio , Neumonía/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Nicotiana/efectos adversosRESUMEN
Haemoglobin H (HbH) disease is a type of non-transfusion-dependent thalassaemia. This cross-sectional study aimed at determining the prevalence and severity of liver iron overload and liver fibrosis in patients with HbH disease. Risk factors for advanced liver fibrosis were also identified. A total of 80 patients were evaluated [median (range) age 53 (24-79) years, male 34%, non-deletional HbH disease 24%]. Patients underwent 'observed' T2-weighted magnetic resonance imaging examination for liver iron concentration (LIC) quantification, and transient elastography for liver stiffness measurement (LSM) and fibrosis staging. In all, 25 patients (31%) had moderate-to-severe liver iron overload (LIC ≥7 mg/g dry weight). The median LIC was higher in non-deletional than in deletional HbH disease (7·8 vs. 2.9 mg/g dry weight, P = 0·002). In all, 16 patients (20%) had advanced liver fibrosis (LSM >7.9 kPa) and seven (9%) out of them had probable cirrhosis (LSM >11.9 kPa). LSM positively correlated with age (R = 0·24, P = 0·03), serum ferritin (R = 0·36, P = 0·001) and LIC (R = 0·28, P = 0·01). In multivariable regression, age ≥65 years [odds ratio (OR) 4·97, 95% confidence interval (CI) 1·52-17·50; P = 0·047] and moderate-to-severe liver iron overload (OR 3·47, 95% CI 1·01-12·14; P = 0·01) were independently associated with advanced liver fibrosis. The findings suggest that regular screening for liver complications should be considered in the management of HbH disease.
Asunto(s)
Hepatopatías/etiología , Talasemia alfa/complicaciones , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Hierro/análisis , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/patología , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Hepatopatías/patología , Masculino , Persona de Mediana Edad , Adulto Joven , Talasemia alfa/patologíaRESUMEN
Consumption of diet rich in fat and cigarette smoking (CS) are independent risk factors of non-alcoholic steatohepatitis (NASH), and they often occur together in some populations. The present study investigated the mechanisms of high-fat diet (HFD) and CS, individually and in combination, on the pathogenesis of NASH in mice. C57BL/6 male mice were subjected to either a low-fat chow (CH) or HFD with or without mainstream CS-exposure (4 cigarettes/day, 5 days/ week for 14 weeks). HFD alone caused hepatosteatosis (2.5-fold increase in TG content) and a significant increase in 3-nitrotyrisine (by â¼40-fold) but without an indication of liver injury, inflammation or fibrosis. CS alone in CH-fed mice increased in Tnfα expression and macrophage infiltration by 2-fold and relatively less increase in 3-nitrotyrosine (18-fold). Combination of HFD and CS precipitated hepatosteatosis to NASH reflected by exacerbated makers of liver inflammation and fibrosis which were associated with much severe liver oxidative stress (90-fold increase in 3-nitrotyrisine along with 6-fold increase in carbonylated proteins and 56% increase in lipid oxidations). Further studies were performed to administer the antioxidant tempol to CS exposed HFD mice and the results showed that the inhibition of liver oxidative stress prevented inflammatory and fibrotic changes in liver despite persisting hepatosteatosis. Our findings suggest that oxidative stress is a key mechanism underlying CS-promoted progression of simple hepatosteatosis to NASH. Targeting hepatic oxidative stress may be a viable strategy in halting the progression of metabolic associated fatty liver disease.
Asunto(s)
Cirrosis Hepática/etiología , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Estrés Oxidativo , Contaminación por Humo de Tabaco/efectos adversos , Animales , Antioxidantes/farmacología , Óxidos N-Cíclicos/farmacología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Interleucina-1beta/metabolismo , Peroxidación de Lípido , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/prevención & control , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Estrés Oxidativo/efectos de los fármacos , Carbonilación Proteica , Marcadores de Spin , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease negatively impacts quality of life and survival. Cigarette smoking (CS) is the major risk factor for chronic obstructive pulmonary disease and skeletal muscle dysfunction; however, how CS affects skeletal muscle function remains enigmatic. To examine the impact of CS on skeletal muscle inflammation and regeneration, male BALB/c mice were exposed to CS for 8 weeks before muscle injury was induced by barium chloride injection, and were maintained on the CS protocol for up to 21 days after injury. Barium chloride injection resulted in architectural damage to the tibialis anterior muscle, resulting in a decrease contractile function, which was worsened by CS exposure. CS exposure caused muscle atrophy (reduction in gross weight and myofiber cross-sectional area) and altered fiber type composition (31% reduction of oxidative fibers). Both contractile function and loss in myofiber cross-sectional area by CS exposure gradually recovered over time. Satellite cells are muscle stem cells that confer skeletal muscle the plasticity to adapt to changing demands. CS exposure blunted Pax7+ centralized nuclei within satellite cells and thus prevented the activation of these muscle stem cells. Finally, CS triggered muscle inflammation; in particular, there was an exacerbated recruitment of F4/80+ monocytic cells to the site of injury along with enhanced proinflammatory cytokine expression. In conclusion, CS exposure amplified the local inflammatory response at the site of skeletal muscle injury, and this was associated with impaired satellite cell activation, leading to a worsened muscle injury and contractile function without detectable impacts on the recovery outcomes.
Asunto(s)
Fumar Cigarrillos/efectos adversos , Músculo Esquelético/lesiones , Músculo Esquelético/metabolismo , Regeneración/fisiología , Animales , Masculino , Ratones Endogámicos BALB C , Contracción Muscular/fisiología , Fibras Musculares Esqueléticas/metabolismo , Enfermedades Musculares/metabolismo , Factor de Transcripción PAX7/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Calidad de Vida , Fumar/fisiopatologíaRESUMEN
Cigarette smoking (CS) is known to reduce body weight and this often masks its real effect on insulin action. The present study tested the hypothesis that CS can divert lipid deposition to muscles to offset the supposed benefit of reduced body weight gain on insulin signalling in this major site for glucose tolerance (or insulin action). The study was conducted in mice exposed to chronic CS followed by either a chow (CH) diet or a high-fat (HF) diet. CS increased triglyceride (TG) levels in both plasma and muscle despite a reduced body weight gain and adiposity. CS led to glucose intolerance in CH-fed mice and they retained the glucose intolerance that was induced by the HF diet. In adipose tissue, CS increased macrophage infiltration and the mRNA expression of TNFα but suppressed the protein expression of adipose triglyceride lipase and PPARγ. While CS increased hormone-sensitive lipase and suppressed the mRNA expression of leptin, these effects were blunted in HF-fed mice. These results imply that CS impairs insulin signalling in skeletal muscle via accumulated intramuscular lipids from lipolysis and lipodystrophy of adipose tissues. This may explain why smokers may not benefit from insulin sensitising effects of reduced body weight gain.
Asunto(s)
Fumar Cigarrillos/efectos adversos , Insulina/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Aumento de Peso/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Fumar Cigarrillos/genética , Fumar Cigarrillos/metabolismo , Fumar Cigarrillos/fisiopatología , Dieta Alta en Grasa/efectos adversos , Glucosa/metabolismo , Humanos , Lipólisis , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/genética , Obesidad/fisiopatología , PPAR gamma/genética , PPAR gamma/metabolismo , Triglicéridos/metabolismoRESUMEN
Gastrointestinal (GI) dysfunction is a common comorbidity of chronic obstructive pulmonary disease (COPD) for which a major cause is cigarette smoking (CS). The underlying mechanisms and precise effects of CS on gut contractility, however, are not fully characterised. Therefore, the aim of the present study was to investigate whether CS impacts GI function and structure in a mouse model of CS-induced COPD. We also aimed to investigate GI function in the presence of ebselen, an antioxidant that has shown beneficial effects on lung inflammation resulting from CS exposure. Mice were exposed to CS for 2 or 6 months. GI structure was analysed by histology and immunofluorescence. After 2 months of CS exposure, ex vivo gut motility was analysed using video-imaging techniques to examine changes in colonic migrating motor complexes (CMMCs). CS decreased colon length in mice. Mice exposed to CS for 2 months had a higher frequency of CMMCs and a reduced resting colonic diameter but no change in enteric neuron numbers. Ten days cessation after 2 months CS reversed CMMC frequency changes but not the reduced colonic diameter phenotype. Ebselen treatment reversed the CS-induced reduction in colonic diameter. After 6 months CS, the number of myenteric nitric-oxide producing neurons was significantly reduced. This is the first evidence of colonic dysmotility in a mouse model of CS-induced COPD. Dysmotility after 2 months CS is not due to altered neuron numbers; however, prolonged CS-exposure significantly reduced enteric neuron numbers in mice. Further research is needed to assess potential therapeutic applications of ebselen in GI dysfunction in COPD.
Asunto(s)
Azoles/farmacología , Fumar Cigarrillos/efectos adversos , Tracto Gastrointestinal/fisiopatología , Compuestos de Organoselenio/farmacología , Animales , Recuento de Células , Forma de la Célula/efectos de los fármacos , Colon/efectos de los fármacos , Colon/patología , Colon/fisiopatología , Sistema Nervioso Entérico/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/patología , Isoindoles , Macrófagos/efectos de los fármacos , Masculino , Ratones Endogámicos BALB C , Moco/efectos de los fármacos , Moco/metabolismo , Plexo Mientérico/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismoRESUMEN
Magnetic Resonance Imaging (MRI) is a non-invasive diagnostic tool that provides excellent soft-tissue contrast without the use of ionizing radiation. Compared to other clinical imaging modalities (e.g., CT or ultrasound), however, the data acquisition process for MRI is inherently slow, which motivates undersampling and thus drives the need for accurate, efficient reconstruction methods from undersampled datasets. In this article, we describe the use of "plug-and-play" (PnP) algorithms for MRI image recovery. We first describe the linearly approximated inverse problem encountered in MRI. Then we review several PnP methods, where the unifying commonality is to iteratively call a denoising subroutine as one step of a larger optimization-inspired algorithm. Next, we describe how the result of the PnP method can be interpreted as a solution to an equilibrium equation, allowing convergence analysis from the equilibrium perspective. Finally, we present illustrative examples of PnP methods applied to MRI image recovery.
RESUMEN
Quanta Image Sensor (QIS) is a single-photon detector designed for extremely low light imaging conditions. Majority of the existing QIS prototypes are monochrome based on single-photon avalanche diodes (SPAD). Passive color imaging has not been demonstrated with single-photon detectors due to the intrinsic difficulty of shrinking the pixel size and increasing the spatial resolution while maintaining acceptable intra-pixel cross-talk. In this paper, we present image reconstruction of the first color QIS with a resolution of 1024 × 1024 pixels, supporting both single-bit and multi-bit photon counting capability. Our color image reconstruction is enabled by a customized joint demosaicing-denoising algorithm, leveraging truncated Poisson statistics andvariance stabilizing transforms. Experimental results of the new sensor and algorithm demonstrate superior color imaging performance for very low-light conditions with a mean exposure of as low as a few photons per pixel in both real and simulated images.
RESUMEN
Inositol-requiring enzyme 1 alpha (IRE1α) is an endoplasmic reticulum (ER)-transmembrane endonuclease that is activated in response to ER stress as part of the unfolded protein response (UPR). Chronic activation of the UPR has been implicated in the pathogenesis of many common diseases including diabetes, cancer, and neurological pathologies such as Huntington's and Alzheimer's disease. 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (4µ8C) is widely used as a specific inhibitor of IRE1α ribonuclease activity (IC50 of 6.89â µM in cultured cells). However, in this paper, we demonstrate that 4µ8C acts as a potent reactive oxygen species (ROS) scavenger, both in a cell-free assay and in cultured cells, at concentrations lower than that widely used to inhibit IRE1α activity. In vitro we show that, 4µ8C effectively decreases xanthine/xanthine oxidase catalysed superoxide production with an IC50 of 0.2â µM whereas in cultured endothelial and clonal pancreatic ß-cells, 4µ8C inhibits angiotensin II-induced ROS production with IC50 values of 1.92 and 0.29â µM, respectively. In light of this discovery, conclusions reached using 4µ8C as an inhibitor of IRE1α should be carefully evaluated. However, this unexpected off-target effect of 4µ8C may prove therapeutically advantageous for the treatment of pathologies that are thought to be caused by, or exacerbated by, both oxidative and ER stress such as endothelial dysfunction and/or diabetes.
Asunto(s)
Antioxidantes/farmacología , Endorribonucleasas/antagonistas & inhibidores , Himecromona/análogos & derivados , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Células Cultivadas , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Himecromona/farmacología , Ratones , Especies Reactivas de Oxígeno/metabolismo , Ribonucleasas/antagonistas & inhibidores , Respuesta de Proteína Desplegada/efectos de los fármacosRESUMEN
The accumulation of unfolded proteins within the endoplasmic reticulum (ER) causes ER stress and activation of unfolded protein response (UPR). This response can trigger ER-associated degradation and autophagy, which clear unfolded proteins and restore protein homeostasis. Recently, it has become clear that ubiquitination plays an important role in the regulation of autophagy. In the present study, we investigated how the E3 ubiquitin ligase neural precursor cell-expressed, developmentally down-regulated protein 4-2 (Nedd4-2) interacts with ER stress and autophagy. In mice, we found that an increase in the expression of Nedd4-2, which was concomitant with the activation of the UPR and autophagy, was caused by a prolonged high-fructose and high-fat diet that induces ER stress in the liver. Pharmacologic induction of ER stress also led to an increase in Nedd4-2 expression in cultured cells, which was coincident with UPR and autophagy activation. The inhibition of inositol-requiring enzyme 1 significantly suppressed Nedd4-2 expression. Moreover, increased Nedd4-2 expression in vivo was closely associated with the activation of inositol-requiring enzyme 1 and increased expression of the spliced form of X-box binding protein 1. Furthermore, knockdown of Nedd4-2 in cultured cells suppressed both basal autophagy and ER stress-induced autophagy, whereas overexpression of Nedd4-2-induced autophagy. Taken together, our findings provide evidence that Nedd4-2 is up-regulated in response to ER stress by the spliced form of X-box binding protein 1 and that this is important in the induction of an appropriate autophagic response.-Wang, H. Sun, R.-Q., Camera, D., Zeng, X.-Y., Jo, E., Chan, S. M. H., Herbert, T. P., Molero, J. C., Ye, J.-M. Endoplasmic reticulum stress up-regulates Nedd4-2 to induce autophagy.
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Autofagia/fisiología , Retículo Endoplásmico/fisiología , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Regulación de la Expresión Génica/fisiología , Ubiquitina-Proteína Ligasas/metabolismo , Regulación hacia Arriba/fisiología , Animales , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Fibroblastos/metabolismo , Células HEK293 , Células HeLa , Humanos , Hígado/metabolismo , Masculino , Ratones , Ubiquitina-Proteína Ligasas Nedd4 , Ubiquitina-Proteína Ligasas/genética , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
Hepatic steatosis is often associated with insulin resistance as a hallmark of the metabolic syndrome in the liver. The present study investigated the effects of PPARα activation induced by fenofibrate (FB) on the relationship of insulin resistance and hepatic steatosis in mice fed a high-fat (HF) diet, which increases lipid influx into the liver. Mice were fed HF diet to induce insulin resistance and hepatic steatosis with or without FB. FB activated PPARα and ameliorated HF diet-induced glucose intolerance and hepatic insulin resistance without altering either hepatic steatosis or inflammation signaling (JNK or IKK). Interestingly, FB treatment simultaneously increased fatty acid (FA) synthesis (50%) and oxidation (66%, both p<0.01) into intermediate lipid metabolites, suggesting a FA oxidation-synthesis cycling in operation. Associated with these effects, diacylglycerols (DAGs) were sequestered within the lipid droplet/ER compartment, thus reducing their deposition in the cellular membrane, which is known to impair insulin signal transduction. These findings suggest that the reduction in membrane DAGs (rather than total hepatic steatosis) may be critical for the protection by fenofibrate-induced PPARα activation against hepatic insulin resistance induced by dietary fat.
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Diglicéridos/metabolismo , Retículo Endoplásmico/metabolismo , Hígado Graso/metabolismo , Fenofibrato/farmacología , Hipolipemiantes/farmacología , Insulina/metabolismo , Gotas Lipídicas/metabolismo , Animales , Dieta Alta en Grasa/efectos adversos , Retículo Endoplásmico/efectos de los fármacos , Hígado Graso/etiología , Gotas Lipídicas/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , PPAR alfa/metabolismo , Transducción de SeñalRESUMEN
The unfolded protein response (UPR) pathways have been implicated in the development of hepatic insulin resistance during high fructose (HFru) feeding. The present study investigated their roles in initiating impaired insulin signaling transduction in the liver induced by HFru feeding in mice. HFru feeding resulted in hepatic steatosis, increased de novo lipogenesis and activation of two arms of the UPR pathways (IRE1/XBP1 and PERK/eIF2α) in similar patterns from 3days to 8weeks. In order to identify the earliest trigger of impaired insulin signaling in the liver, we fed mice a HFru diet for one day and revealed that only the IRE1 branch was activated (by 2-fold) and insulin-mediated Akt phosphorylation was blunted (~25%) in the liver. There were significant increases in phosphorylation of JNK (~50%) and IRS at serine site (~50%), protein content of ACC and FAS (up to 2.5-fold) and triglyceride level (2-fold) in liver (but not in muscle or fat). Blocking IRE1 activity abolished increases in JNK activity, IRS serine phosphorylation and protected insulin-stimulated Akt phosphorylation without altering hepatic steatosis or PKCε activity, a key link between lipids and insulin resistance. Our findings together suggest that activation of IRE1-JNK pathway is a key linker of impaired hepatic insulin signaling transduction induced by HFru feeding.
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Fructosa/administración & dosificación , Fructosa/metabolismo , Insulina/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/fisiología , Triglicéridos/metabolismo , Animales , Resistencia a la Insulina , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Proteínas Serina-Treonina Quinasas/genética , Respuesta de Proteína DesplegadaRESUMEN
A quanta image sensor (QIS) is a class of single-photon imaging devices that measure light intensity using oversampled binary observations. Because of the stochastic nature of the photon arrivals, data acquired by QIS is a massive stream of random binary bits. The goal of image reconstruction is to recover the underlying image from these bits. In this paper, we present a non-iterative image reconstruction algorithm for QIS. Unlike existing reconstruction methods that formulate the problem from an optimization perspective, the new algorithm directly recovers the images through a pair of nonlinear transformations and an off-the-shelf image denoising algorithm. By skipping the usual optimization procedure, we achieve orders of magnitude improvement in speed and even better image reconstruction quality. We validate the new algorithm on synthetic datasets, as well as real videos collected by one-bit single-photon avalanche diode (SPAD) cameras.
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OBJECTIVE: To assess the incremental diagnostic value of spine MRI evaluated separately from and combined with sacroiliac joint (SIJ) MRI in non-radiographic axial spondyloarthritis (nr-axSpA) compared with SIJ MRI alone. METHODS: The study sample comprised two independent cohorts A/B of 130 consecutive patients aged ≤50 years with back pain, newly referred to two university clinics, and 20 healthy controls. Patients were classified according to clinical examination and pelvic radiographs as having nr-axSpA (n=50), ankylosing spondylitis (n=33), or non-specific back pain (n=47). Four readers assessed SIJ and spine MRI separately 6â months apart, and 1-12â months later both scans simultaneously using standardised modules. Readers recorded presence/absence of SpA and their level of confidence in this conclusion on a 0-10 scale (0=definitely not; 10=definite). We analysed differences between SIJ MRI versus spine MRI alone, and SIJ MRI alone versus combined MRI, descriptively by the number/percentage of subjects according to the mean of four readers. RESULTS: In cohorts A/B, 15.8%/24.2% of patients with nr-axSpA having a negative SIJ MRI were reclassified as being positive for SpA by global evaluation of combined scans. However, 26.8%/11.4% of non-specific back pain controls and 17.5% of healthy volunteers with a negative SIJ MRI were falsely reclassified as having SpA by combined MRI. Low confidence in a diagnosis of SpA by SIJ MRI increased to high confidence by combined MRI in 6.6%/7.3% of patients with nr-axSpA. CONCLUSIONS: Combined spine and SIJ MRI added little incremental value compared with SIJ MRI alone for diagnosing patients with nr-axSpA and enhancing confidence in this diagnosis.
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Articulación Sacroiliaca/patología , Columna Vertebral/patología , Espondilitis Anquilosante/diagnóstico , Adolescente , Adulto , Dolor de Espalda/etiología , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Radiografía , Articulación Sacroiliaca/diagnóstico por imagen , Columna Vertebral/diagnóstico por imagen , Espondiloartritis/complicaciones , Espondiloartritis/diagnóstico , Espondilitis Anquilosante/complicaciones , Adulto JovenRESUMEN
OBJECTIVE: To determine candidate lesion-based criteria for a positive sacroiliac joint (SIJ) MRI based on bone marrow oedema (BMO) and/or erosion in non-radiographic axial spondyloarthritis (nr-axSpA); to compare the performance of lesion-based criteria with global evaluation by expert readers. METHODS: Two independent cohorts A/B of 69/88 consecutive patients with back pain aged ≤50â years, with median symptom duration 1.3/10.0â years, were referred for suspected SpA (A) or acute anterior uveitis plus back pain (B). Patients were classified according to rheumatologist expert opinion based on clinical examination, pelvic radiography and laboratory values as having nr-axSpA (n=51), ankylosing spondylitis (n=34) or non-specific back pain (n=72). Four blinded readers assessed SIJ MRI, recording the presence/absence of SpA by concomitant global evaluation of T1-weighted spin echo (T1SE) and short τ inversion recovery (STIR) scans and, thereafter, whether BMO and/or erosion were present/absent in each SIJ quadrant of each MRI slice. We derived candidate lesion-based criteria based on the number of SIJ quadrants with BMO and/or erosion and calculated mean sensitivity and specificity for SpA. RESULTS: For both cohorts A/B, global assessment showed high specificity (0.95/0.83) compared with the Assessment in SpondyloArthritis international Society (ASAS) definition (0.76/0.74). BMO ≥3 (0.89/0.84) or ≥4 (0.92/0.87) showed comparably high specificity to global assessment. Erosion ≥2 and/or BMO ≥3 or ≥4 were associated with comparably high sensitivity to global assessment without affecting specificity. These combined criteria showed both higher sensitivity and specificity than the ASAS definition. CONCLUSIONS: Lesion-based criteria for a positive SIJ MRI based on both BMO and/or erosion performed best for classification of axial SpA, reflecting the contextual information provided by T1SE and STIR sequences.
Asunto(s)
Dolor de Espalda/patología , Médula Ósea/patología , Edema/patología , Articulación Sacroiliaca/patología , Sacroileítis/patología , Espondilitis Anquilosante/patología , Adulto , Dolor de Espalda/etiología , Estudios de Cohortes , Edema/etiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Sacroileítis/complicaciones , Sensibilidad y Especificidad , Espondiloartropatías/complicaciones , Espondiloartropatías/patología , Espondilitis Anquilosante/complicaciones , Uveítis Anterior/complicacionesRESUMEN
OBJECTIVE: To present the 3-year experience of using venovenous extracorporeal membrane oxygenation for patients with severe respiratory failure in a single centre in Hong Kong. DESIGN: Case series. SETTING: A 19-bed Intensive Care Unit of a tertiary hospital in Hong Kong. PATIENTS: All patients who were managed with venovenous extracorporeal membrane oxygenation from 1 July 2010 to 30 June 2013 in the Intensive Care Unit. RESULTS: Overall, 31 patients (mean age, 42.2 years, standard deviation, 14.1 years; 21 males) received venovenous extracorporeal membrane oxygenation for the treatment of severe respiratory failure. Of these, 90.3% (28 patients) presented with pneumonia as the cause of the respiratory failure, and 22 of them had identifiable causes. A total of nine (29.0%) patients were diagnosed to have H1N1 infection. The median Murray score was 3.5 (interquartile range, 3.0-3.5); the median duration of venovenous extracorporeal membrane oxygenation support was 5.0 (2.8-8.6) days; and the median duration of mechanical ventilator support was 18.2 (7.8-27.9) days. The overall intensive care unit mortality was 19.4% (n=6). The overall in-hospital mortality and the 28-day mortality were both 22.6% (n=7). Among the 22 patients who had identifiable infective causes, those suffering from viral infection had lower intensive care unit and hospital mortality than those who had bacterial infection (8.3% vs 20.0%). All the H1N1 patients survived. Complications related to extracorporeal membrane oxygenation included severe bleeding (n=2; 6.5%) and mechanical complications of the circuits (n=3; 9.7%). CONCLUSIONS: Venovenous extracorporeal membrane oxygenation is an effective adjunctive therapy and can be used as a life-saving procedure for carefully selected patients with severe acute respiratory distress syndrome when the limits of standard therapy have been reached.