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1.
Circ Res ; 134(6): 748-769, 2024 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-38484026

RESUMO

Mammalian physiology and cellular function are subject to significant oscillations over the course of every 24-hour day. It is likely that these daily rhythms will affect function as well as mechanisms of disease in the central nervous system. In this review, we attempt to survey and synthesize emerging studies that investigate how circadian biology may influence the neurovascular unit. We examine how circadian clocks may operate in neural, glial, and vascular compartments, review how circadian mechanisms regulate cell-cell signaling, assess interactions with aging and vascular comorbidities, and finally ask whether and how circadian effects and disruptions in rhythms may influence the risk and progression of pathophysiology in cerebrovascular disease. Overcoming identified challenges and leveraging opportunities for future research might support the development of novel circadian-based treatments for stroke.


Assuntos
Relógios Circadianos , Ritmo Circadiano , Animais , Envelhecimento/fisiologia , Mamíferos
2.
Nature ; 582(7812): 395-398, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32494010

RESUMO

Neuroprotectant strategies that have worked in rodent models of stroke have failed to provide protection in clinical trials. Here we show that the opposite circadian cycles in nocturnal rodents versus diurnal humans1,2 may contribute to this failure in translation. We tested three independent neuroprotective approaches-normobaric hyperoxia, the free radical scavenger α-phenyl-butyl-tert-nitrone (αPBN), and the N-methyl-D-aspartic acid (NMDA) antagonist MK801-in mouse and rat models of focal cerebral ischaemia. All three treatments reduced infarction in day-time (inactive phase) rodent models of stroke, but not in night-time (active phase) rodent models of stroke, which match the phase (active, day-time) during which most strokes occur in clinical trials. Laser-speckle imaging showed that the penumbra of cerebral ischaemia was narrower in the active-phase mouse model than in the inactive-phase model. The smaller penumbra was associated with a lower density of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive dying cells and reduced infarct growth from 12 to 72 h. When we induced circadian-like cycles in primary mouse neurons, deprivation of oxygen and glucose triggered a smaller release of glutamate and reactive oxygen species, as well as lower activation of apoptotic and necroptotic mediators, in 'active-phase' than in 'inactive-phase' rodent neurons. αPBN and MK801 reduced neuronal death only in 'inactive-phase' neurons. These findings suggest that the influence of circadian rhythm on neuroprotection must be considered for translational studies in stroke and central nervous system diseases.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Modelos Animais de Doenças , Neurônios/patologia , Neuroproteção , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/prevenção & controle , Animais , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/prevenção & controle , Glucose/deficiência , Humanos , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Acidente Vascular Cerebral/fisiopatologia , Pesquisa Translacional Biomédica , Falha de Tratamento
3.
Nature ; 583(7814): E14, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32533095

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

4.
Stroke ; 55(7): 1904-1913, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38913800

RESUMO

BACKGROUND: The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPRmt may be a potential therapeutic target for ischemic stroke. METHODS: We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPRmt. We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro. RESULTS: Inducing UPRmt with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPRmt could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPRmt with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPRmt in vivo, which reduced infarction and improved neurological outcomes. CONCLUSIONS: These findings suggest that the UPRmt is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPRmt mechanism may provide a new therapeutic avenue for ischemic stroke.


Assuntos
Isquemia Encefálica , Glucose , Mitocôndrias , Neurônios , Resposta a Proteínas não Dobradas , Animais , Masculino , Camundongos , Isquemia Encefálica/metabolismo , Células Cultivadas , Glucose/deficiência , Infarto da Artéria Cerebral Média/metabolismo , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oxigênio/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacos
5.
Stroke ; 55(6): 1650-1659, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38738428

RESUMO

BACKGROUND: Beyond neuronal injury, cell death pathways may also contribute to vascular injury after stroke. We examined protein networks linked to major cell death pathways and identified SLC22A17 (solute carrier family 22 member 17) as a novel mediator that regulates endothelial tight junctions after ischemia and inflammatory stress. METHODS: Protein-protein interactions and brain enrichment analyses were performed using STRING, Cytoscape, and a human tissue-specific expression RNA-seq database. In vivo experiments were performed using mouse models of transient focal cerebral ischemia. Human stroke brain tissues were used to detect SLC22A17 by immunostaining. In vitro experiments were performed using human brain endothelial cultures subjected to inflammatory stress. Immunostaining and Western blot were used to assess responses in SLC22A17 and endothelial tight junctional proteins. Water content, dextran permeability, and electrical resistance assays were used to assess edema and blood-brain barrier (BBB) integrity. Gain and loss-of-function studies were performed using lentiviral overexpression of SLC22A17 or short interfering RNA against SLC22A17, respectively. RESULTS: Protein-protein interaction analysis showed that core proteins from apoptosis, necroptosis, ferroptosis, and autophagy cell death pathways were closely linked. Among the 20 proteins identified in the network, the iron-handling solute carrier SLC22A17 emerged as the mediator enriched in the brain. After cerebral ischemia in vivo, endothelial expression of SLC22A17 increases in both human and mouse brains along with BBB leakage. In human brain endothelial cultures, short interfering RNA against SLC22A17 prevents TNF-α (tumor necrosis factor alpha)-induced ferroptosis and downregulation in tight junction proteins and disruption in transcellular permeability. Notably, SLC22A17 could repress the transcription of tight junctional genes. Finally, short interfering RNA against SLC22A17 ameliorates BBB leakage in a mouse model of focal cerebral ischemia. CONCLUSIONS: Using a combination of cell culture, human stroke samples, and mouse models, our data suggest that SLC22A17 may play a role in the control of BBB function after cerebral ischemia. These findings may offer a novel mechanism and target for ameliorating BBB injury and edema after stroke.


Assuntos
Barreira Hematoencefálica , Isquemia Encefálica , Junções Íntimas , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Isquemia Encefálica/genética , Morte Celular , Células Endoteliais/metabolismo , Camundongos Endogâmicos C57BL , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Junções Íntimas/metabolismo
6.
Artigo em Inglês | MEDLINE | ID: mdl-38985201

RESUMO

BACKGROUND: Service delivery of post-treatment surveillance in head and neck cancer (HNC) varies across institutions in Australia. To better understand current practices and develop protocols that maximize service capacity or incorporate emerging technologies, especially in under-resourced regional and remote communities, it is important to obtain the perspectives of clinicians that regularly manage patients with HNC. DESIGN: This cross-sectional study utilized an online survey distributed via email to specialists recruited from HNC-associated networks across Australia. The survey captured information on current practices and explored clinician perspectives towards re-designing the current surveillance model to incorporate telehealth or patient-reported outcome measures (PROMs). Quantitative data was analyzed using descriptive statistics while open-ended survey comments were analyzed using a content analysis approach. RESULTS: Forty participants completed the survey (25 surgeons, 9 medical oncologists, 5 radiation oncologists and 1 oral medicine specialist). Most clinicians used either institution-specific guidelines (44%) or National Comprehensive Cancer Network guidelines (39%), with the remaining 17% using surveillance intervals based on patient symptoms. Following treatment, 53% of participants imaged patients only when there was clinical suspicion of recurrence or new symptoms. Planned surveillance imaging was conducted at 6 or 12-monthly intervals based on the HNC subtype. Fifty-seven percent of clinicians were open to redesigning the surveillance model, specifically in low-risk patients who did not require nasoendoscopic examination. Seventy-one percent had concerns regarding the feasibility of telehealth appointments, citing disparities in digital health equity. Additionally, 61% felt PROMs are currently underutilized and were open to incorporating HNC-specific PROMS into surveillance. Open-ended responses indicated that within the current surveillance model, "fragmented service provision" and "administration issues" were significantly impacting on timing of care. CONCLUSION: Surveyed HNC clinicians feel that current post-treatment surveillance can be fragmented and potentially lead to delayed care. They are open to incorporating PROMS to assist in surveillance scheduling, especially in low-risk patients.

7.
J Neurosci ; 42(12): 2418-2432, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35105673

RESUMO

Repetitive mild traumatic brain injury (mTBI) in children and adolescents leads to acute and chronic neurologic sequelae and is linked to later life neurodegenerative disease. However, the biological mechanisms connecting early life mTBI to neurodegeneration remain unknown. Using an adolescent mouse repetitive closed head injury model that induces progressive cognitive impairment in males and anxiety in females in the absence of overt histopathology, we examined transcriptional and translational changes in neurons isolated from sham and injured brain in the chronic phase after injury. At 14 months, single-nuclei RNA sequencing of cortical brain tissue identified disruption of genes associated with neuronal proteostasis and evidence for disrupted ligand-receptor signaling networks in injured mice. Western blot analysis of isolated neurons showed evidence of inflammasome activation and downstream IL-1ß processing, as previously demonstrated in acute CNS injury models, and accumulation of misfolded, hyperphosphorylated tau, and changes in expression of proteins suggestive of impaired translation in males but not in females. At 6 months, injured IL-1 receptor 1 (IL-1R1) KO mice, which are protected from postinjury cognitive deficits, had decreased accumulation of pro-IL-1ß and misfolded tau in cortex and cerebellum, suggesting that IL-1R1 is upstream of inflammasome priming (defined as increase in pro-IL-1ß) and abnormal tau phosphorylation. Together, our findings provide evidence for neuronal inflammasome activation and impaired proteostasis as key mechanisms linking repetitive mTBI in adolescence to later life neurologic dysfunction and neurodegeneration.SIGNIFICANCE STATEMENT Repetitive mild closed head injury in adolescent male mice leads to impaired proteostasis, tau phosphorylation, and inflammasome activation in neurons later in adulthood through mechanisms involving IL-1 receptor 1. The data are the first to link repetitive mild traumatic brain injury in adolescence to neurodegeneration and suggest molecular targets and pathways to prevent neurologic sequelae in the chronic period after injuries.


Assuntos
Concussão Encefálica , Doenças Neurodegenerativas , Tauopatias , Animais , Concussão Encefálica/complicações , Concussão Encefálica/patologia , Modelos Animais de Doenças , Feminino , Inflamassomos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias , Proteostase , Receptores de Interleucina-1 , Tauopatias/patologia
8.
J Neurochem ; 167(4): 571-581, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37874764

RESUMO

In the central nervous system, microglia are responsible for removing infectious agents, damaged/dead cells, and amyloid plaques by phagocytosis. Other cell types, such as astrocytes, are also recently recognized to show phagocytotic activity under some conditions. Oligodendrocyte precursor cells (OPCs), which belong to the same glial cell family as microglia and astrocytes, may have similar functions. However, it remains largely unknown whether OPCs exhibit phagocytic activity against foreign materials like microglia. To answer this question, we examined the phagocytosis activity of OPCs using primary rat OPC cultures. Since innate phagocytosis activity could trigger cell death pathways, we also investigated whether participating in phagocytosis activity may lead to OPC cell death. Our data shows that cultured OPCs phagocytosed myelin-debris-rich lysates prepared from rat corpus callosum, without progressing to cell death. In contrast to OPCs, mature oligodendrocytes did not show phagocytotic activity against the bait. OPCs also exhibited phagocytosis towards lysates of rat brain cortex and cell membrane debris from cultured astrocytes, but the percentage of OPCs that phagocytosed beta-amyloid was much lower than the myelin debris. We then conducted RNA-seq experiments to examine the transcriptome profile of OPC cultures and found that myelination- and migration-associated genes were downregulated 24 h after phagocytosis. On the other hand, there were a few upregulated genes in OPCs 24 h after phagocytosis. These data confirm that OPCs play a role in debris removal and suggest that OPCs may remain in a quiescent state after phagocytosis.


Assuntos
Células Precursoras de Oligodendrócitos , Ratos , Animais , Células Precursoras de Oligodendrócitos/fisiologia , Diferenciação Celular/fisiologia , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Fagocitose/genética , Células Cultivadas
9.
Neurobiol Dis ; 181: 106120, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37044366

RESUMO

The neurovascular unit is where two very distinct physiological systems meet: The central nervous system (CNS) and the blood. The permeability of the barriers separating these systems is regulated by time, including both the 24 h circadian clock and the longer processes of aging. An endogenous circadian rhythm regulates the transport of molecules across the blood-brain barrier and the circulation of the cerebrospinal fluid and the glymphatic system. These fluid dynamics change with time of day, and with age, and especially in the context of neurodegeneration. Factors may differ depending on brain region, as can be highlighted by consideration of circadian regulation of the neurovascular niche in white matter. As an example of a potential target for clinical applications, we highlight chaperone-mediated autophagy as one mechanism at the intersection of circadian dysregulation, aging and neurodegenerative disease. In this review we emphasize key areas for future research.


Assuntos
Relógios Circadianos , Doenças Neurodegenerativas , Substância Branca , Humanos , Relógios Circadianos/fisiologia , Envelhecimento/fisiologia , Ritmo Circadiano/fisiologia
10.
Eur Arch Otorhinolaryngol ; 280(2): 885-890, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36136151

RESUMO

PURPOSE: To investigate parental perceptions of the effects of tonsillectomy on their child's quality of life while awaiting and following surgery in an Australian public health system. METHODS: An observational pragmatic study was undertaken at a tertiary Australian hospital. Parents of paediatric patients (2-16 years of age) listed for tonsillectomy completed a validated quality-of-life questionnaire (T-14 Paediatric Throat Disorders Outcome Test) at the initial consultation, on day of surgery, 6 weeks post-operatively and 6 months post-operatively. T-14 scores were compared using the Related-Samples Wilcoxon Signed Rank Test. RESULTS: Parents of 167 children participated in this study. There was a median wait time of 174 days (IQR 108-347) from the initial consultation until the day of surgery, with no significant change in median T-14 scores (35 [IQR 22-42] vs 36 [IQR 22-42]; n = 63; p > 0.05). There was a significant decrease from pre-operative T-14 scores to 6 weeks post-operatively (33.5 [IQR 22-42] vs 2 [IQR 0-5]; n = 160; p < 0.001), and this was sustained with a minor improvement at 6 months post-operatively (6 weeks 2 [IQR 0-5] vs 6 months 0 [IQR 0-2]; n = 148; p < 0.001). CONCLUSIONS: Paediatric tonsillectomy improves quality of life with a sustained benefit in the long term. There is no improvement to the patient's quality of life while awaiting tonsillectomy, thus patient welfare can be improved through reducing waiting times for surgery.


Assuntos
Tonsilectomia , Criança , Humanos , Recém-Nascido , Adenoidectomia , Qualidade de Vida , Austrália , Faringe
11.
J Stroke Cerebrovasc Dis ; 32(7): 107106, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37116446

RESUMO

OBJECTIVES: To delineate diurnal variation onset distinguishing ischemic from hemorrhagic stroke, wake from sleep onset, and weekdays from weekends/holidays. MATERIALS AND METHODS: We analyzed patients enrolled in the FAST-MAG trial of field-initiated neuroprotective agent in patients with hyperacute stroke within 2h of symptoms onset. Stroke onset times were analyzed in 1h, 4h, and 12h time blocks throughout the 24h day-night cycle. Patient demographic, clinical features, stroke severity, and prehospital workflow were evaluated for association with onset times. RESULTS: Among 1615 acute cerebrovascular disease patients, final diagnoses were acute cerebral ischemia in 76.5% and Intracerebral hemorrhage in 23.5%. Considering all acute cerebrovascular disease patients, frequency of wake onset times showed a bimodal pattern, with peaks on onsets at 09:00-13:59 and 17:00-18:59 and early morning (00:00-05:59) onset in only 3.8%. Circadian rhythmicity differed among stroke subtypes: in acute cerebral ischemia, a single broad plateau of elevated incidences was seen from 10:00-21:59; in Intracerebral hemorrhage, bimodal peaks occurred at 09:00 and 19:00. The ratio of Intracerebral hemorrhage to acute cerebral ischemia occurrence was highest in early morning, 02:00-06:59. Marked weekday vs weekends pattern variation was noted for acute cerebral ischemia, with a broad plateau between 09:00 and 21:59 on weekdays but a unimodal peak at 14:00-15:59 on weekends. CONCLUSIONS: Wake onset of acute cerebrovascular disease showed a marked circadian variation, with distinctive patterns of a broad elevated plateau among acute cerebral ischemia patients; a bimodal peak among intracerebral hemorrhage patients; and a weekend change in acute cerebral ischemia pattern to a unimodal peak.


Assuntos
Isquemia Encefálica , Transtornos Cerebrovasculares , Acidente Vascular Cerebral Hemorrágico , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral Hemorrágico/diagnóstico , Acidente Vascular Cerebral Hemorrágico/complicações , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/terapia , Acidente Vascular Cerebral/complicações , Hemorragia Cerebral/epidemiologia , Transtornos Cerebrovasculares/etiologia
12.
Clin Otolaryngol ; 48(4): 672-679, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37129013

RESUMO

OBJECTIVE: To determine primary and secondary post-tonsillectomy haemorrhage (PTH) rates and identify predictive factors in a cohort of consecutive adult and paediatric BiZact™ tonsillectomy cases. SETTING: Retrospective cohort study. Patients from Flinders Medical Centre, Noarlunga Hospital and private otolaryngology practices who underwent BiZact™ tonsillectomy from 2017 to 2020. DATA COLLECTED: patient age, indication for tonsillectomy, surgeon experience, time and severity of PTH, including return to theatre. Each secondary PTH was graded using the Stammberger classification. Logistic regression was utilised to identify predictors of secondary PTH. RESULTS: One thousand seven hundred and seventeen patient medical records were assessed (658 adults and 1059 children). The primary PTH rate was 0.1%, and secondary PTH rate was 5.9%. The majority of secondary PTH cases were Stammberger grade A (80/102, 78.4%) requiring observation only. Few secondary PTH required medical intervention (grade B; 9/102, 8.8%), return to theatre (grade C; 12/102, 11.8%), or blood transfusion (grade D; 1/102, 1.0%), with no death reported (grade E; 0/102, 0.0%). Recurrent secondary PTH occurred in 8 patients (0.5%). Predictive factors of secondary PTH in children were surgeon experience with trainees having greater chance of PTH (OR 2.502, 95% CI 1.345-4.654; p = .004) and age of child (OR 1.095, 95% CI 1.025-1.170; p = .007). Surgeon experience was a predictive factor for adults (OR 3.804, 95% CI 2.139-6.674; p < .001). CONCLUSIONS: BiZact™ tonsillectomy has a low primary PTH rate, with a secondary PTH rate comparable to other 'hot tonsillectomy' techniques. The majority of PTH events were minor and self-reported. There appears to be a learning curve for trainee surgeons.


Assuntos
Cirurgiões , Tonsilectomia , Adulto , Criança , Humanos , Tonsilectomia/métodos , Estudos Retrospectivos , Hemorragia Pós-Operatória/cirurgia
13.
Stroke ; 53(12): e507-e511, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36321457

RESUMO

BACKGROUND: The immune response to acute cerebral ischemia is a major factor in stroke pathobiology. Circadian biology modulates some aspects of immune response. The goal of this study is to compare key parameters of immune response during the active/awake phase versus inactive/sleep phase in a mouse model of transient focal cerebral ischemia. METHODS: Mice were housed in normal or reversed light cycle rooms for 3 weeks, and then they were blindly subjected to transient focal cerebral ischemia. Flow cytometry was used to examine immune responses in blood, spleen, and brain at 3 days after ischemic onset. RESULTS: In blood, there were higher levels of circulating T cells in mice subjected to focal ischemia during zeitgeber time (ZT)1-3 (inactive or sleep phase) versus ZT13-15 mice (active or awake phase). In the spleen, organ weight and immune cell numbers were lower in ZT1-3 versus ZT13-15 mice. Consistent with these results, there was an increased infiltration of activated T cells into brain at ZT1-3 compared with ZT13-15. CONCLUSIONS: This proof-of-concept study indicates that there are significant diurnal effects on the immune response after focal cerebral ischemia in mice. Hence, therapeutic strategies focused on immune targets should be reassessed to account for the effects of diurnal rhythms and circadian biology in nocturnal rodent models of stroke.


Assuntos
Isquemia Encefálica , Ataque Isquêmico Transitório , Acidente Vascular Cerebral , Animais , Camundongos , Baço , Camundongos Endogâmicos C57BL , Encéfalo , Infarto Cerebral , Isquemia , Imunidade
14.
Stroke ; 53(12): 3741-3750, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36252110

RESUMO

BACKGROUND: It has been reported that the S1P (sphingosine 1-phosphate) receptor modulator fingolimod reduces infarction in rodent models of stroke. Recent studies have suggested that circadian rhythms affect stroke and neuroprotection. Therefore, this study revisited the use of fingolimod in mouse focal cerebral ischemia to test the hypothesis that efficacy might depend on whether experiments were performed during the inactive sleep or active wake phases of the circadian cycle. METHODS: Two different stroke models were implemented in male C57Bl/6 mice-transient middle cerebral artery occlusion and permanent distal middle cerebral artery occlusion. Occlusion occurred either during inactive or active circadian phases. Mice were treated with 1 mg/kg fingolimod at 30- or 60-minute postocclusion and 1 day later for permanent and transient middle cerebral artery occlusion, respectively. Infarct volume, brain swelling, hemorrhagic transformation, and behavioral outcome were assessed at 2 or 3 days poststroke. Three independent experiments were performed in 2 different laboratories. RESULTS: Fingolimod decreased peripheral lymphocyte number in naive mice, as expected. However, it did not significantly affect infarct volume, brain swelling, hemorrhagic transformation, or behavioral outcome at 2 or 3 days after transient or permanent focal cerebral ischemia during inactive or active circadian phases of stroke onset. CONCLUSIONS: Outcomes were not improved by fingolimod in either transient or permanent focal cerebral ischemia during both active and inactive circadian phases. These negative findings suggest that further testing of fingolimod in clinical trials may not be warranted unless translational studies can identify factors associated with fingolimod's efficacy or lack thereof.


Assuntos
Edema Encefálico , Isquemia Encefálica , Acidente Vascular Cerebral , Animais , Camundongos , Masculino , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Edema Encefálico/tratamento farmacológico , Esfingosina , Acidente Vascular Cerebral/tratamento farmacológico , Camundongos Endogâmicos C57BL , Hemorragia/tratamento farmacológico , Modelos Animais de Doenças
15.
PLoS Med ; 19(2): e1003910, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35120123

RESUMO

BACKGROUND: Preclinical data suggest circadian variation in ischemic stroke progression, with more active cell death and infarct growth in rodent models with inactive phase (daytime) than active phase (nighttime) stroke onset. We aimed to examine the association of stroke onset time with presenting severity, early neurological deterioration (END), and long-term functional outcome in human ischemic stroke. METHODS AND FINDINGS: In a Korean nationwide multicenter observational cohort study from May 2011 to July 2020, we assessed circadian effects on initial stroke severity (National Institutes of Health Stroke Scale [NIHSS] score at admission), END, and favorable functional outcome (3-month modified Rankin Scale [mRS] score 0 to 2 versus 3 to 6). We included 17,461 consecutive patients with witnessed ischemic stroke within 6 hours of onset. Stroke onset time was divided into 2 groups (day-onset [06:00 to 18:00] versus night-onset [18:00 to 06:00]) and into 6 groups by 4-hour intervals. We used mixed-effects ordered or logistic regression models while accounting for clustering by hospitals. Mean age was 66.9 (SD 13.4) years, and 6,900 (39.5%) were women. END occurred in 2,219 (12.7%) patients. After adjusting for covariates including age, sex, previous stroke, prestroke mRS score, admission NIHSS score, hypertension, diabetes, hyperlipidemia, smoking, atrial fibrillation, prestroke antiplatelet use, prestroke statin use, revascularization, season of stroke onset, and time from onset to hospital arrival, night-onset stroke was more prone to END (adjusted incidence 14.4% versus 12.8%, p = 0.006) and had a lower likelihood of favorable outcome (adjusted odds ratio, 0.88 [95% CI, 0.79 to 0.98]; p = 0.03) compared with day-onset stroke. When stroke onset times were grouped by 4-hour intervals, a monotonic gradient in presenting NIHSS score was noted, rising from a nadir in 06:00 to 10:00 to a peak in 02:00 to 06:00. The 18:00 to 22:00 and 22:00 to 02:00 onset stroke patients were more likely to experience END than the 06:00 to 10:00 onset stroke patients. At 3 months, there was a monotonic gradient in the rate of favorable functional outcome, falling from a peak at 06:00 to 10:00 to a nadir at 22:00 to 02:00. Study limitations include the lack of information on sleep disorders and patient work/activity schedules. CONCLUSIONS: Night-onset strokes, compared with day-onset strokes, are associated with higher presenting neurologic severity, more frequent END, and worse 3-month functional outcome. These findings suggest that circadian time of onset is an important additional variable for inclusion in epidemiologic natural history studies and in treatment trials of neuroprotective and reperfusion agents for acute ischemic stroke.


Assuntos
Ritmo Circadiano/fisiologia , Progressão da Doença , AVC Isquêmico/epidemiologia , AVC Isquêmico/fisiopatologia , Gravidade do Paciente , Recuperação de Função Fisiológica/fisiologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , AVC Isquêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , República da Coreia/epidemiologia , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
16.
BMC Microbiol ; 22(1): 24, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-35026986

RESUMO

BACKGROUND: Otitis media (OM) is a major disease burden in Australian Aboriginal children, contributing to serious long-term health outcomes. We report a pilot analysis of OM in children attending an outreach ear and hearing clinic in a remote south Australian community over a two-year period. Our study focuses on longitudinal relationships between ear canal microbiota characteristics with nasopharyngeal microbiota, and clinical and treatment variables. RESULTS: Middle ear health status were assessed in 19 children (aged 3 months to 8 years) presenting in remote western South Australia and medical interventions were recorded. Over the two-year study period, chronic suppurative OM was diagnosed at least once in 7 children (37%), acute OM with perforation in 4 children (21%), OM with effusion in 11 children (58%), while only 1 child had no ear disease. Microbiota analysis of 19 children (51 sets of left and right ear canal swabs and nasopharyngeal swabs) revealed a core group of bacterial taxa that included Corynebacterium, Alloiococcus, Staphylococcus, Haemophilus, Turicella, Streptococcus, and Pseudomonas. Within-subject microbiota similarity (between ears) was significantly greater than inter-subject similarity, regardless of differences in ear disease (p = 0.0006). Longitudinal analysis revealed changes in diagnosis to be associated with more pronounced changes in microbiota characteristics, irrespective of time interval. Ear microbiota characteristics differed significantly according to diagnosis (P (perm) = 0.0001). Diagnoses featuring inflammation with tympanic membrane perforation clustering separately to those in which the tympanic membrane was intact, and characterised by increased Proteobacteria, particularly Haemophilus influenzae, Moraxella catarrhalis, and Oligella. While nasopharyngeal microbiota differed significantly in composition to ear microbiota (P (perm) = 0.0001), inter-site similarity was significantly greater in subjects with perforated tympanic membranes, a relationship that was associated with the relative abundance of H. influenzae in ear samples (rs = - 0.71, p = 0.0003). Longitudinal changes in ear microbiology reflected changes in clinical signs and treatment. CONCLUSIONS: Children attending the ear and hearing clinic in a remote Aboriginal community present with a broad spectrum of OM conditions and severities, consistent with other remote Aboriginal communities. Ear microbiota characteristics align with OM diagnosis and change with disease course. Nasopharyngeal microbiota characteristics are consistent with the contribution of acute upper respiratory infection to OM aetiology.


Assuntos
Bactérias/isolamento & purificação , Orelha Média/microbiologia , Orelha Média/patologia , Microbiota , Havaiano Nativo ou Outro Ilhéu do Pacífico/estatística & dados numéricos , Otite Média/microbiologia , Austrália/epidemiologia , Bactérias/classificação , Bactérias/genética , Bactérias/patogenicidade , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Nasofaringe/microbiologia , Otite Média/epidemiologia , Projetos Piloto , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/microbiologia , População Rural/estatística & dados numéricos
17.
Nature ; 535(7613): 551-5, 2016 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-27466127

RESUMO

Neurons can release damaged mitochondria and transfer them to astrocytes for disposal and recycling. This ability to exchange mitochondria may represent a potential mode of cell-to-cell signalling in the central nervous system. Here we show that astrocytes in mice can also release functional mitochondria that enter neurons. Astrocytic release of extracellular mitochondrial particles was mediated by a calcium-dependent mechanism involving CD38 and cyclic ADP ribose signalling. Transient focal cerebral ischaemia in mice induced entry of astrocytic mitochondria into adjacent neurons, and this entry amplified cell survival signals. Suppression of CD38 signalling by short interfering RNA reduced extracellular mitochondria transfer and worsened neurological outcomes. These findings suggest a new mitochondrial mechanism of neuroglial crosstalk that may contribute to endogenous neuroprotective and neurorecovery mechanisms after stroke.


Assuntos
Astrócitos/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/patologia , Acidente Vascular Cerebral/patologia , ADP-Ribosil Ciclase 1/deficiência , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/metabolismo , Animais , Astrócitos/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Cálcio/metabolismo , Sobrevivência Celular , ADP-Ribose Cíclica/metabolismo , Masculino , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Neurônios/metabolismo , Fatores de Proteção , RNA Interferente Pequeno/genética , Transdução de Sinais , Estresse Fisiológico , Acidente Vascular Cerebral/metabolismo
18.
Handb Exp Pharmacol ; 273: 267-293, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33580391

RESUMO

The brain microenvironment is tightly regulated. The blood-brain barrier (BBB), which is composed of cerebral endothelial cells, astrocytes, and pericytes, plays an important role in maintaining the brain homeostasis by regulating the transport of both beneficial and detrimental substances between circulating blood and brain parenchyma. After brain injury and disease, BBB tightness becomes dysregulated, thus leading to inflammation and secondary brain damage. In this chapter, we overview the fundamental mechanisms of BBB damage and repair after stroke and traumatic brain injury (TBI). Understanding these mechanisms may lead to therapeutic opportunities for brain injury.


Assuntos
Lesões Encefálicas , Acidente Vascular Cerebral , Barreira Hematoencefálica , Células Endoteliais , Humanos , Pericitos
19.
Int J Mol Sci ; 23(4)2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35216347

RESUMO

Oligodendrocyte precursor cells (OPCs) serve as progenitor cells of terminally differentiated oligodendrocytes. Past studies have confirmed the importance of epigenetic system in OPC differentiation to oligodendrocytes. High mobility group A1 (HMGA1) is a small non-histone nuclear protein that binds DNA and modifies the chromatin conformational state. However, it is still completely unknown about the roles of HMGA1 in the process of OPC differentiation. In this study, we prepared primary OPC cultures from the neonatal rat cortex and examined whether the loss- and gain-of-function of HMGA1 would change the mRNA levels of oligodendrocyte markers, such as Cnp, Mbp, Myrf and Plp during the process of OPC differentiation. In our system, the mRNA levels of Cnp, Mbp, Myrf and Plp increased depending on the oligodendrocyte maturation step, but the level of Hmga1 mRNA decreased. When HMGA1 was knocked down by a siRNA approach, the mRNA levels of Cnp, Mbp, Myrf and Plp were smaller in OPCs with Hmga1 siRNA compared to the ones in the control OPCs. On the contrary, when HMGA1 expression was increased by transfection of the Hmga1 plasmid, the mRNA levels of Cnp, Mbp, Myrf and Plp were slightly larger compared to the ones in the control OPCs. These data may suggest that HMGA1 participates in the process of OPC differentiation by regulating the mRNA expression level of myelin-related genes.


Assuntos
Marcadores Genéticos/genética , Proteína HMGA1a/genética , Células Precursoras de Oligodendrócitos/metabolismo , Transcrição Gênica/genética , Animais , Diferenciação Celular/genética , Bainha de Mielina/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Ratos , Células-Tronco/metabolismo
20.
Medicina (Kaunas) ; 58(2)2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35208469

RESUMO

Background and Objectives: In head and neck cancer, delays in time to treatment are associated with poorer clinical outcomes. Within Australia, it is recommended that primary treatment is initiated within 56 days of initial referral. The aim of this study was to assess whether head and neck cancer treatment was delivered within these timeframe guidelines at our institution and identify factors associated with treatment delays. Methods: This retrospective cohort study assessed patients newly diagnosed with head and neck cancer over a 24 months period (2018 to 2019) at Flinders Medical Centre, Australia. Time to treatment intervals were calculated for comparison to local timeframe guidelines. Results: A total of 72 patients met the inclusion criteria. The median time from specialist referral to treatment initiation was 45.5 days (IQR 29-61), with 72% meeting the 56 days guideline. On univariate logistic regression, patients undergoing primary radiotherapy treatment were less likely to meet this guideline than those undergoing primary surgery (OR 8.8, 95% CI 2.6-28.9, p < 0.001), as were those requiring prophylactic gastrostomy tube insertion (OR 3.1, 95% CI 1.1-9.0, p < 0.05). Treatment initiation beyond 56 days had no significant impact on 12 months overall survival or disease-free survival. Conclusions: The findings of this study demonstrate that primary radiotherapy treatment is associated with delays in head and neck cancer treatment initiation, likely related to time consuming pre-treatment factors such as gastrostomy tube insertion.


Assuntos
Gastrostomia , Neoplasias de Cabeça e Pescoço , Austrália/epidemiologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Estudos Retrospectivos , Austrália do Sul
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