RESUMEN
Excessive sitting is detrimentally associated with cardiovascular disease and all-cause mortality. Frequent breaks in prolonged sitting can improve cardiometabolic responses in non-stroke populations. However, this has not been established in stroke survivors. This study will determine the most effective dose of activity breaks that (i) produce clinically meaningful improvements in mean systolic blood pressure (primary outcome), postprandial glucose, and insulin responses (secondary outcomes), and (ii) is safe and feasible. We hypothesis that systolic blood pressure, postprandial insulin, and glucose responses will improve with increasing doses of activity and be most effective at the maximum safe and feasible dose of activity. Thirty participants in the most effective dose will provide 80% power to detect a within-person, between-condition, difference of 3.5â¯mmHg in systolic blood pressure assuming a SD of 15â¯mmHg, within-person correlation of 0.9, and αâ¯=â¯0.05. Stroke survivors will complete 3 experimental conditions in a within-participant, dose escalation design including (i) uninterrupted sitting (8â¯h), (ii) Dose 1: uninterrupted sitting with bouts of light-intensity exercises while standing (initial dose involves two 5-min breaks), and (iii) Dose 2: two additional 5-min breaks above Dose 1. Ambulatory blood pressure will be collected every 30â¯min during experimental conditions and hourly for 24-h post-experimental conditions. Blood samples will be collected every 30â¯min during 2-h postprandial periods. This study will identify the most effective dose of light-intensity exercises while standing to improve cardiometabolic responses in stroke survivors.
RESUMEN
OBJECTIVES: People with stroke sit for long periods each day, which may compromise blood glucose control and increase risk of recurrent stroke. Studies in other populations have found regular activity breaks have a significant immediate (within-day) positive effect on glucose metabolism. We examined the effects of breaking up uninterrupted sitting with frequent, short bouts of light-intensity physical activity in people with stroke on post-prandial plasma glucose and insulin. METHODS: Randomized within-participant crossover trial. We included people between 3 months and 10 years post-stroke, ambulant with minimal assistance and not taking diabetic medication other than metformin. The three experimental conditions (completed in random order) were: sitting for 8 h uninterrupted, sitting with 3 min bouts of light-intensity exercise while standing every 30 min, or sitting with 3 min of walking every 30 min. Meals were standardized and bloods were collected half- to one-hourly via an intravenous cannula. RESULTS: A total of 19 participants (9 female, mean [SD] age 68.2 [10.2]) completed the trial. The majority ( n = 12, 63%) had mild stroke symptoms (National Institutes of Stroke Scale score 0-13). There was no significant effect of experimental condition on glucose (mean [SD] positive incremental area [+iAUC] mmol·L·h-1 under the curve during sitting 42.3 [29.5], standing 47.4 [23.1], walking 44.6 [26.5], p = 0.563) or insulin (mean + iAUC pmol·L·h-1 sitting 14,161 [7,560], standing 14,043 [8,312], walking 14,008 [8,269], p = 0.987). CONCLUSION: Frequent, short bouts of light-intensity physical activity did not have a significant effect on post-prandial plasma glucose and insulin in this sample of people with stroke. Further studies are needed to identify strategies that improve inactivity-related glucose metabolism after stroke.
Asunto(s)
Ejercicio Físico/fisiología , Conducta Sedentaria , Sedestación , Accidente Cerebrovascular/fisiopatología , Anciano , Anciano de 80 o más Años , Glucemia/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Periodo Posprandial/fisiología , Caminata/fisiologíaRESUMEN
Binary image thresholding is the most commonly used technique to quantitatively examine changes in immunolabelled material. In this article we demonstrate that if implicit assumptions predicating this technique are not met then the resulting analysis and data interpretation can be incorrect. We then propose a transparent approach to image quantification that is straightforward to execute using currently available software and therefore can be readily and cost-effectively implemented.
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Técnica del Anticuerpo Fluorescente/métodos , Inmunohistoquímica/métodos , Animales , RatasRESUMEN
Cerebral ischemia results in damage to neuronal circuits and lasting impairment in function. We have previously reported that stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors with the ampakine, CX1837, increases brain-derived neurotrophic factor (BDNF) levels and affords significant motor recovery after stroke in young mice. Here, we investigated whether administration of CX1837 in aged (24 months old) mice was equally effective. In a model of focal ischemia, administration of CX1837 from 5 days after stroke resulted in a small gain of motor function by week 6 after stroke. Mice that received a local delivery of BDNF via hydrogel implanted into the stroke cavity also showed a small gain of function from 4 to 6 weeks after stroke. Combining both treatments, however, resulted in a marked improvement in motor function from 2 weeks after insult. Assessment of peri-infarct tissue 2 weeks after stroke revealed a significant increase in p-AKT and p-CREB after the combined drug treatment. Using the pan-AKT inhibitor, GSK-690693, or deletion of CREB from forebrain neurons using the CREB-flox/CAMKii-cre mice, we were able to block the recovery of motor function. These data suggest that combined CX1837 and local delivery of BDNF are required to achieve maximal functional recovery after stroke in aged mice, and is occurring via the AKT-GSK3-CREB signaling pathway.
Asunto(s)
Isquemia Encefálica , Factor Neurotrófico Derivado del Encéfalo/farmacología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Propionatos/farmacología , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal/efectos de los fármacos , Accidente Cerebrovascular , Animales , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Isquemia Encefálica/fisiopatología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Masculino , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Recuperación de la Función/efectos de los fármacos , Transducción de Señal/genética , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/fisiopatologíaRESUMEN
Microglia are unique cells within the central nervous system because of their biophysical independence. As a result of this unusual property the cells must undergo significant structural remodelling in order to engage and connect with other elements within the central nervous system. Efficient remodelling is required for all activities that microglia are involved in ranging from monitoring synaptic information flow through to phagocytosis of tissue debris. Despite the fact that morphological remodelling is a pre-requisite to all microglial activities, relatively little research has been undertaken on the topic. This review examines what is known about how microglia transform themselves during development, under physiological conditions in response to changes in neuronal activity, and under pathological circumstances. Specific attention is given to exploring a variety of models that have been proposed to account for microglial transformation as well as the signals that are known to trigger these transformations.
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Microglía/citología , Microglía/fisiología , Animales , Humanos , Modelos Neurológicos , Enfermedades del Sistema Nervioso/patologíaRESUMEN
Recently, it has been discovered that the working memory deficits induced by exposure to chronic stress can be prevented by treating stressed animals with minocycline, a putative inhibitor of microglial activity. One of the pressing issues that now requires clarification is exactly how exposure to chronic stress modifies microglial morphology, this being a significant issue as microglial morphology is tightly coupled with their function. To examine how chronic stress alters microglial morphology, we digitally reconstructed microglia within the rat medial prefrontal cortex. Our analysis revealed that stress increased the internal complexity of microglia, enhancing ramification (i.e. branching) without altering the overall area occupied by the cell and that this effect was more pronounced in larger cells. We subsequently determined that minocycline treatment largely abolished the pro-ramifying effects of stress. With respect to mechanisms, we could not find any evidence of increased inflammation or neurodegeneration (interleukin-1ß, MHC-II, CD68, terminal deoxynucleotidyl transferase dUTP nick end labeling, and activated caspase-3). We did, however, find that chronic stress markedly increased the expression of ß1-integrin (CD29), a protein previously implicated in microglial ramification. Together, these findings highlight that increased ramification of microglia may represent an important neurobiological mechanism through which microglia mediate the behavioral effects of chronic psychological stress.
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Microglía/citología , Minociclina/farmacología , Corteza Prefrontal/citología , Estrés Fisiológico/fisiología , Animales , Masculino , Microglía/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Exposure to social stress has been linked to the development and maintenance of mood-related psychopathology; however, the underlying neurobiological changes remain uncertain. In this study, we examined numbers of δFosB-immunoreactive cells in the forebrains of rats subjected to 12 episodes of social defeat. This was achieved using the social conflict model whereby animals are introduced into the home cage of older males ("residents") trained to attack and defeat all such "intruders"; importantly, controls were treated identically except that the resident was absent. Our results indicated that the only region in which δFosB-positive cells were found in significantly higher numbers in intruders than in controls was the infralimbic medial prefrontal cortex (mPFC). This same effect was not apparent using another psychological stressor, noise stress. Cells of the infralimbic mPFC also displayed evidence of chromatin remodeling. We found that exposure to repeated episodes of social defeat increased numbers of cells immunoreactive for histone H3 acetylation, but not for histone H3 phosphoacetylation, in the infralimbic mPFC. Collectively, these findings highlight the importance of the infralimbic mPFC in responding to social stress-a finding that provides insight into the possible neurobiological alterations associated with stress-induced psychiatric illness.
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Regulación de la Expresión Génica/fisiología , Histonas/metabolismo , Corteza Prefrontal/fisiología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Conducta Social , Acetilación , Análisis de Varianza , Animales , Conducta Animal , Recuento de Células/métodos , Lisina/metabolismo , Masculino , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Corteza Prefrontal/citología , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/metabolismo , Estrés Psicológico/patología , Estrés Psicológico/fisiopatologíaRESUMEN
Evidence suggests that exposure to bacterial endotoxin in early life can alter the production of pro-inflammatory cytokines in later life. This phenomenon may have significant consequences for pain and pain related behaviours as pro-inflammatory cytokines heighten pain sensitivity. This association has yet to be examined. As such, the aim of the present study was to characterize pain behaviours in adult rat offspring following prenatal endotoxin (PE) exposure. Pregnant F344 rats received endotoxin (200microg/kg, s.c.) or saline on gestational days 16, 18 and 20. Pain thresholds were assessed in the adult PE offspring (n=23) and control offspring (n=24) prior to and 4h following administration of lipopolysaccharide (LPS; 100microg/kg, s.c.). Three assays of pain were employed - the hot plate, tail immersion and von Frey tests. Results demonstrated sex-specific effects of prenatal endotoxin on the offspring, with PE males displaying unaltered pain thresholds on the von Frey test post-LPS administration (p<0.01), while male control offspring (n=24) displayed the expected hyperalgesia. Male PE offspring also displayed increased pain thresholds on the tail immersion test (p<0.01), while no change in pain sensitivity was observed in control males following LPS exposure. No difference in response was observed between the female PE and control offspring on the von Frey test, however PE female offspring displayed increased thresholds on the tail immersion test compared to baseline - an effect not observed in the control female offspring. Pain sensitivity on the hot plate test was unaffected by prenatal exposure to endotoxin. These data suggest that prenatal exposure to products associated with bacterial infection have the capacity to alter pain responses, which are evident in the adult offspring.
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Endotoxinas , Lipopolisacáridos/farmacología , Umbral del Dolor/efectos de los fármacos , Dolor/fisiopatología , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Análisis de Varianza , Animales , Animales Recién Nacidos , Conducta Animal , Peso Corporal/efectos de los fármacos , Femenino , Tamaño de la Camada/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Dimensión del Dolor/métodos , Embarazo , Ratas , Ratas Endogámicas F344 , Tiempo de Reacción/efectos de los fármacos , Reflejo de Sobresalto , Factores SexualesRESUMEN
This article provides a brief commentary on Pfaff et al's timely review of the relations between mechanisms of CNS arousal and mechanisms of stress. Pfaff and colleagues use the review as a platform to propose the existence of a coherent stress-arousal state. We suggest that this proposal is, on a number of grounds, flawed. In turn, we counter that the while the states of stress and arousal are related they are as entities fundamentally separate. Moreover, we propose that any productive attempt to unite the two states must acknowledge the importance of and therefore centrally include higher order integrative phenomena, such as, appraisal.