RESUMO
Visual loss in acute optic neuritis is typically attributed to axonal conduction block due to inflammatory demyelination, but the mechanisms remain unclear. Recent research has highlighted tissue hypoxia as an important cause of neurological deficits and tissue damage in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) and, here, we examine whether the optic nerves are hypoxic in experimental optic neuritis induced in Dark Agouti rats. At both the first and second peaks of disease expression, inflamed optic nerves labelled significantly for tissue hypoxia (namely, positive for hypoxia inducible factor-1α (HIF1α) and intravenously administered pimonidazole). Acutely inflamed nerves were also labelled significantly for innate markers of oxidative and nitrative stress and damage, including superoxide, nitric oxide and 3-nitrotyrosine. The density and diameter of capillaries were also increased. We conclude that in acute optic neuritis, the optic nerves are hypoxic and come under oxidative and nitrative stress and damage. Tissue hypoxia can cause mitochondrial failure and thus explains visual loss due to axonal conduction block. Tissue hypoxia can also induce a damaging oxidative and nitrative environment. The findings indicate that treatment to prevent tissue hypoxia in acute optic neuritis may help to restore vision and protect from damaging reactive oxygen and nitrogen species.
Assuntos
Encefalomielite Autoimune Experimental , Neurite Óptica , Ratos , Animais , Camundongos , Neurite Óptica/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Nervo Óptico/metabolismo , Hipóxia/metabolismo , Fatores Imunológicos/metabolismo , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: With growing rates of unregulated drug toxicity death and concerns regarding COVID-19 transmission among people who use drugs, in March 2020, prescribed safer supply guidance was released in British Columbia. This study describes demographic and substance use characteristics associated with obtaining prescribed safer supply and examines the association between last 6-month harm reduction service access and obtaining prescribed safer supply. METHODS: Data come from the 2021 Harm Reduction Client Survey administered at 17 harm reduction sites across British Columbia. The sample included all who self-reported use of opioids, stimulants, or benzodiazepines in the prior 3 days (N = 491), given active use of these drugs was a requirement for eligibility for prescribed safer supply. The dependent variable was obtaining a prescribed safer supply prescription (Yes vs. No). The primary independent variables were access to drug checking services and access to overdose prevention services in the last 6 months (Yes vs. No). Descriptive statistics (Chi-square tests) were used to compare the characteristics of people who did and did not obtain a prescribed safer supply prescription. Multivariable logistic regression models were run to examine the association of drug checking services and overdose prevention services access with obtaining prescribed safer supply. RESULTS: A small proportion (n = 81(16.5%)) of the sample obtained prescribed safer supply. After adjusting for gender, age, and urbanicity, people who reported drug checking services access in the last 6 months had 1.67 (95% CI 1.00-2.79) times the odds of obtaining prescribed safer supply compared to people who had not contacted these services, and people who reported last 6 months of overdose prevention services access had more than twice the odds (OR 2.08 (95% CI 1.20-3.60)) of prescribed safer supply access, compared to people who did not access these services. CONCLUSIONS: Overall, the proportion of respondents who received prescribed safer supply was low, suggesting that this intervention is not reaching all those in need. Harm reduction services may serve as a point of contact for referral to prescribed safer supply. Additional outreach strategies and service models are needed to improve the accessibility of harm reduction services and of prescribed safer supply in British Columbia.
Assuntos
Overdose de Drogas , Redução do Dano , Humanos , Estudos Transversais , Analgésicos Opioides , Benzodiazepinas , Colúmbia Britânica , Overdose de Drogas/prevenção & controleRESUMO
BACKGROUND: Encephalopathy can occur from a non-fatal toxic drug event (overdose) which results in a partial or complete loss of oxygen to the brain, or due to long-term substance use issues. It can be categorized as a non-traumatic acquired brain injury or toxic encephalopathy. In the context of the drug toxicity crisis in British Columbia (BC), Canada, measuring the co-occurrence of encephalopathy and drug toxicity is challenging due to lack of standardized screening. We aimed to estimate the prevalence of encephalopathy among people who experienced a toxic drug event and examine the association between toxic drug events and encephalopathy. METHODS: Using a 20% random sample of BC residents from administrative health data, we conducted a cross-sectional analysis. Toxic drug events were identified using the BC Provincial Overdose Cohort definition and encephalopathy was identified using ICD codes from hospitalization, emergency department, and primary care records between January 1st 2015 and December 31st 2019. Unadjusted and adjusted log-binomial regression models were employed to estimate the risk of encephalopathy among people who had a toxic drug event compared to people who did not experience a toxic drug event. RESULTS: Among people with encephalopathy, 14.6% (n = 54) had one or more drug toxicity events between 2015 and 2019. After adjusting for sex, age, and mental illness, people who experienced drug toxicity were 15.3 times (95% CI = 11.3, 20.7) more likely to have encephalopathy compared to people who did not experience a drug toxicity event. People who were 40 years and older, male, and had a mental illness were at increased risk of encephalopathy. CONCLUSIONS: There is a need for collaboration between community members, health care providers, and key stakeholders to develop a standardized approach to define, screen, and detect neurocognitive injury related to drug toxicity.
Assuntos
Encefalopatias , Overdose de Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Transtornos Relacionados ao Uso de Substâncias , Humanos , Masculino , Colúmbia Britânica/epidemiologia , Estudos Transversais , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Overdose de Drogas/epidemiologia , Overdose de Drogas/prevenção & controle , Encefalopatias/induzido quimicamente , Encefalopatias/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologiaRESUMO
AIMS: The objective of the study is to explore the importance of tissue hypoxia in causing neurological deficits and demyelination in the inflamed CNS, and the value of inspiratory oxygen treatment, using both active and passive experimental autoimmune encephalomyelitis (EAE). METHODS: Normobaric oxygen treatment was administered to Dark Agouti rats with either active or passive EAE, compared with room air-treated, and naïve, controls. RESULTS: Severe neurological deficits in active EAE were significantly improved after just 1 h of breathing approximately 95% oxygen. The improvement was greater and more persistent when oxygen was applied either prophylactically (from immunisation for 23 days), or therapeutically from the onset of neurological deficits for 24, 48, or 72 h. Therapeutic oxygen for 72 h significantly reduced demyelination and the integrated stress response in oligodendrocytes at the peak of disease, and protected from oligodendrocyte loss, without evidence of increased oxidative damage. T-cell infiltration and cytokine expression in the spinal cord remained similar to that in untreated animals. The severe neurological deficit of animals with passive EAE occurred in conjunction with spinal hypoxia and was significantly reduced by oxygen treatment initiated before their onset. CONCLUSIONS: Severe neurological deficits in both active and passive EAE can be caused by hypoxia and reduced by oxygen treatment. Oxygen treatment also reduces demyelination in active EAE, despite the autoimmune origin of the disease.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Ratos , Animais , Camundongos , Esclerose Múltipla/metabolismo , Medula Espinal/metabolismo , Hipóxia/metabolismo , Oxigênio/metabolismo , Oxigênio/uso terapêutico , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: North America has been experiencing an unprecedented epidemic of drug overdose. This study investigated the associations of drug overdose with the risk of cardiovascular disease (CVD) and 11 major CVD subtypes. METHODS: This nested case-control study was based on a cohort of 20% random sample of residents in British Columbia, Canada, who were aged 18-80 years and did not have known CVD at baseline (n = 617,863). During a 4-year follow-up period, persons who developed incident CVD were identified as case subjects, and the onset date of CVD was defined as the index date. For each case subject, we used incidence density sampling to randomly select up to five control subjects from the cohort members who were alive and did not have known CVD by the index date, were admitted to an emergency department or hospital on the index date for non-CVD causes, and were matched on age, sex, and region of residence. Overdose exposure on the index date and each of the previous 5 days was examined for each subject. RESULTS: This study included 16,113 CVD case subjects (mean age 53 years, 59% male) and 66,875 control subjects. After adjusting for covariates, overdose that occurred on the index date was strongly associated with CVD [odds ratio (OR), 2.9; 95% confidence interval (CI), 2.4-3.5], especially for arrhythmia (OR, 8.6; 95% CI, 6.2-12.0), ischemic stroke (OR, 5.3; 95% CI, 2.0-14.1), hemorrhagic stroke (OR, 3.1; 95% CI, 1.2-8.3), and myocardial infarction (OR, 3.0; 95% CI, 1.5-5.8). The CVD risk was decreased but remained significantly elevated for overdose that occurred on the previous day, and was not observed for overdose that occurred on each of the previous 2-5 days. CONCLUSIONS: Drug overdose appears to be associated with increased risk of cardiovascular diseases.
Assuntos
Doenças Cardiovasculares , Overdose de Drogas , Infarto do Miocárdio , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , Infarto do Miocárdio/epidemiologia , Overdose de Drogas/epidemiologia , Overdose de Drogas/complicações , Fatores de Risco , IncidênciaRESUMO
BACKGROUND: Stimulant use has been rising among people with opioid use disorder in recent years in North America, alongside a parallel rise in illicit drug toxicity (overdose) deaths. This study aimed to examine the association between stimulant use and overdose mortality. METHODS: Data from a universal health insurance client roster were used to identify a 20% random general population sample (aged ≥12) in British Columbia, Canada between January 1 2015 and December 31 2018 (N = 1,089,682). Provincial health records were used to identify people who used opioids and/or stimulants. Fatal overdose observed during follow-up (January 12,015- December 312,018) was retrieved from Vital Statistics Death Registry and BC Coroners Service Data. Potential confounders including age, sex, health region, comorbidities and prescribed medications were retrieved from the provincial client roster and health records. RESULTS: We identified 7460 people who used stimulants and or opioids. During follow-up there were 272 fatal overdose events. People who used both opioids and stimulants had more than twice the hazard of fatal overdose (HR: 2.02, 95% CI: 1.47-2.78, p < 0.001) compared to people who used opioids only. The hazard of death increased over time among people who used both opioids and stimulants. CONCLUSIONS: There is an urgent need to prioritize the service needs of people who use stimulants to reduce overdose mortality in British Columbia. Findings have relevance more broadly in other North American settings, where similar trends in opioid and stimulant polysubstance use have been observed.
Assuntos
Estimulantes do Sistema Nervoso Central , Overdose de Drogas , Transtornos Relacionados ao Uso de Opioides , Humanos , Analgésicos Opioides/efeitos adversos , Estudos de Coortes , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/efeitos adversos , Colúmbia Britânica/epidemiologiaRESUMO
Importance: Studies have suggested a rise in opioid- and stimulant-involved overdoses in recent years in North America. This risk may be acute for individuals who have had contact with the criminal justice system, who are particularly vulnerable to overdose risk. Objective: To examine the association of opioid and/or stimulant use disorder diagnoses with overdose (fatal and nonfatal) among people with histories of incarceration. Design, Setting, and Participants: In this cohort study, population-based health and corrections data were retrieved from the British Columbia Provincial Overdose Cohort, which contains a 20% random sample of residents of British Columbia. The analysis included all people in the 20% random sample who had a history of incarceration between January 1, 2010, and December 31, 2014. Outcomes were derived from 5-years of follow-up data (January 1, 2015, to December 31, 2019). Statistical analysis took place from January 2022 to June 2022. Exposures: Substance use disorder diagnosis type (ie, opioid use disorder, stimulant use disorder, both, or neither), sociodemographic, health, and incarceration characteristics. Main Outcomes and Measures: Hazard ratios (HRs) are reported from an Andersen-Gill model for recurrent nonfatal overdose events and from a Fine and Gray competing risk model for fatal overdose events. Results: The study identified 6816 people (5980 male [87.7%]; 2820 aged <30 years [41.4%]) with histories of incarceration. Of these, 293 (4.3%) had opioid use disorder only, 395 (6.8%) had stimulant use disorder only, and 281 (4.1%) had both diagnoses. During follow-up, 1655 people experienced 4026 overdoses including 3781 (93.9%) nonfatal overdoses, and 245 (6.1%) fatal overdoses. In adjusted analyses, the hazard of both fatal (HR, 2.39; 95% CI, 1.48-3.86) and nonfatal (HR, 2.45; 95% CI, 1.94-3.11) overdose was highest in the group with both opioid and stimulant use disorder diagnoses. Conclusions and Relevance: This cohort study of people with a history of incarceration found an elevated hazard of fatal and nonfatal overdose among people with both opioid and stimulant use disorder diagnoses. This study suggests an urgent need to address the service needs of individuals who have had contact with the criminal justice system and who co-use opioids and stimulants.
Assuntos
Estimulantes do Sistema Nervoso Central , Overdose de Drogas , Transtornos Relacionados ao Uso de Opioides , Masculino , Humanos , Analgésicos Opioides/efeitos adversos , Estudos de Coortes , Overdose de Drogas/epidemiologia , Overdose de Drogas/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/efeitos adversosRESUMO
BACKGROUND: Substance use disorder (SUD) has become increasingly prevalent worldwide, this study investigated the associations of SUD and alcohol, cannabis, opioid, or stimulant use disorder with cardiovascular disease (CVD) and 11 major CVD subtypes. METHODS: This study was based on a 20% random sample of residents in British Columbia, Canada, who were aged 18 - 80 years at baseline on January 1, 2015. Using linked administrative health data during 2010 - 2014, we identified people with various SUDs and prevalent CVDs at baseline, and examined the cross-sectional associations between SUDs and CVDs. After excluding people with CVDs at baseline, we followed the cohort for 4 years to identify people who developed incident CVDs, and examined the longitudinal associations between SUDs and CVDs. RESULTS: The cross-sectional analysis at baseline included 778,771 people (mean age 45 years, 50% male), 13,279 (1.7%) had SUD, and 41,573 (5.3%) had prevalent CVD. After adjusting for covariates, people with SUD were 2.7 (95% confidence interval [CI], 2.5 - 2.8) times more likely than people without SUD to have prevalent CVD. The longitudinal analysis included 617,863 people, 17,360 (2.8%) developed incident CVD during the follow-up period. After adjusting for covariates, people with SUD were 1.7 (95% CI, 1.6 - 1.9) times more likely than people without SUD to develop incident CVD. The cross-sectional and longitudinal associations were more pronounced for people with opioid or stimulant use disorder. CONCLUSIONS: People with SUD are more likely to have prevalent CVD and develop incident CVD compared with people without SUD.
Assuntos
Doenças Cardiovasculares , Estimulantes do Sistema Nervoso Central , Transtornos Relacionados ao Uso de Substâncias , Colúmbia Britânica/epidemiologia , Doenças Cardiovasculares/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Substâncias/epidemiologiaRESUMO
Alzheimer's disease-associated amyloid beta (Aß) proteins accumulate in the outer retina with increasing age and in eyes of age-related macular degeneration (AMD) patients. To study Aß-induced retinopathy, wild-type mice were injected with nanomolar human oligomeric Aß1-42, which recapitulate the Aß burden reported in human donor eyes. In vitro studies investigated the cellular effects of Aß in endothelial and retinal pigment epithelial (RPE) cells. Results show subretinal Aß-induced focal AMD-like pathology within 2 weeks. Aß exposure caused endothelial cell migration, and morphological and barrier alterations to the RPE. Aß co-localized to late-endocytic compartments of RPE cells, which persisted despite attempts to clear it through upregulation of lysosomal cathepsin B, revealing a novel mechanism of lysosomal impairment in retinal degeneration. The rapid upregulation of cathepsin B was out of step with the prolonged accumulation of Aß within lysosomes, and contrasted with enzymatic responses to internalized photoreceptor outer segments (POS). Furthermore, RPE cells exposed to Aß were identified as deficient in cargo-carrying lysosomes at time points that are critical to POS degradation. These findings imply that Aß accumulation within late-endocytic compartments, as well as lysosomal deficiency, impairs RPE function over time, contributing to visual defects seen in aging and AMD eyes.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Lisossomos/metabolismo , Degeneração Macular/metabolismo , Fragmentos de Peptídeos/metabolismo , Fenótipo , Animais , Autofagia/fisiologia , Camundongos , Retina/metabolismo , Doenças Retinianas/metabolismo , Epitélio Pigmentado da Retina/metabolismoRESUMO
BACKGROUND AND AIMS: Reported associations between previous incarceration and the risk of overdose-related death are substantially heterogeneous, and previous studies are limited by an inability to control for confounding factors in risk assessment. This study investigated the associations of overdose-related death with previous incarceration and the number or cumulative duration of previous incarcerations, and individual or neighborhood characteristics that may potentially modify the associations. DESIGN AND SETTING: A cohort study using a 20% random sample of residents in British Columbia, Canada. PARTICIPANTS: A total of 765 690 people aged 23 years or older at baseline as of 1 January 2015. Mean age was 50 years; 49% were males. MEASUREMENTS: Previous incarcerations that occurred during the 5-year exposure period (January 2010 to December 2014) were identified using provincial incarceration records. Overdose-related deaths that occurred during the 3-year follow-up period (January 2015 to December 2017) were identified using linked administrative health data. Baseline individual and neighborhood characteristics were retrieved from the provincial health insurance data. FINDINGS: In the cohort, 5743 people had an incarceration history during the exposure period, and 634 people died from drug overdose during the follow-up period. The mortality rate was 897 and 22 per 100 000 person-years for people who did and did not have an incarceration history, respectively. After adjusting for baseline individual and neighborhood characteristics (without any interaction term), people who had an incarceration history were 4.04 times (95% confidence interval 3.23-5.06) more likely to die from drug overdose compared with people without an incarceration history. The association was stronger for females, people without diagnoses of substance use disorder and people without dispensation of opioids for pain or benzodiazepines (P < 0.001 for each interaction term). There was no discernible linear trend between the number or cumulative duration of previous incarcerations and the risk of overdose-related death. CONCLUSIONS: Previous incarceration appears to be a major risk factor for overdose-related death.
Assuntos
Overdose de Drogas , Prisioneiros , Analgésicos Opioides , Colúmbia Britânica/epidemiologia , Estudos de Coortes , Overdose de Drogas/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: There have been significant efforts to respond to the two public health emergencies of coronavirus disease 2019 (COVID-19) and overdose in British Columbia (BC), Canada. The purpose of this study was to quantify the prevalence of known risk factors associated with mortality due to COVID-19 for persons who have had a non-fatal overdose during 2015-2017 in comparison to persons who have not had an overdose. METHODS: Data were extracted from the BC Provincial Overdose Cohort which includes a 20 % random sample of BC residents and persons who have had a non-fatal overdose in BC from January 2015 to December 2017. Chi-square tests and logistic regression were used to compare risk factors by overdose history. RESULTS: Persons who had a non-fatal overdose were significantly more likely to have three (chronic pulmonary disease, diabetes, coronary heart disease) of the four known chronic conditions associated with the development of severe illness due to COVID-19 compared to persons who did not have a previous non-fatal overdose event. CONCLUSION: Persons who had an overdose were more likely to have several chronic conditions associated with the development of severe illness due to COVID-19. The increased likelihood of having these risk factors is reflective of the social and health inequities experienced by persons who have a history of overdose.
Assuntos
Betacoronavirus , Infecções por Coronavirus/mortalidade , Overdose de Drogas/mortalidade , Pneumonia Viral/mortalidade , Saúde Pública/estatística & dados numéricos , Adulto , Colúmbia Britânica/epidemiologia , COVID-19 , Distribuição de Qui-Quadrado , Estudos de Coortes , Infecções por Coronavirus/complicações , Overdose de Drogas/virologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Prevalência , Projetos de Pesquisa , Fatores de Risco , SARS-CoV-2RESUMO
OBJECTIVE: Treatment of relapses in multiple sclerosis (MS) has not advanced beyond steroid use, which reduces acute loss of function, but has little effect on residual disability. Acute loss of function in an MS model (experimental autoimmune encephalomyelitis [EAE]) is partly due to central nervous system (CNS) hypoxia, and function can promptly improve upon breathing oxygen. Here, we investigate the cause of the hypoxia and whether it is due to a deficit in oxygen supply arising from impaired vascular perfusion. We also explore whether the CNS-selective vasodilating agent, nimodipine, may provide a therapy to restore function, and protect from demyelination in 2 MS models. METHODS: A variety of methods have been used to measure basic cardiovascular physiology, spinal oxygenation, mitochondrial function, and tissue perfusion in EAE. RESULTS: We report that the tissue hypoxia in EAE is associated with a profound hypoperfusion of the inflamed spinal cord. Treatment with nimodipine restores spinal oxygenation and can rapidly improve function. Nimodipine therapy also reduces demyelination in both EAE and a model of the early MS lesion. INTERPRETATION: Loss of function in EAE, and demyelination in EAE, and the model of the early MS lesion, seem to be due, at least in part, to tissue hypoxia due to local spinal hypoperfusion. Therapy to improve blood flow not only protects neurological function but also reduces demyelination. We conclude that nimodipine could be repurposed to offer substantial clinical benefit in MS. ANN NEUROL 2020 ANN NEUROL 2020;88:123-136.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Nimodipina/uso terapêutico , Medula Espinal/patologia , Animais , Progressão da Doença , Encefalomielite Autoimune Experimental/patologia , Feminino , Imageamento por Ressonância Magnética , Masculino , Bainha de Mielina/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Increasing evidence suggests a key role for tissue energy failure in the pathophysiology of multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE), a commonly used model of MS, have been instrumental in illuminating the mechanisms that may be involved in compromising energy production. In this article, we review recent advances in EAE research focussing on factors that conspire to impair tissue energy metabolism, such as tissue hypoxia, mitochondrial dysfunction, production of reactive oxygen/nitrogen species, and sodium dysregulation, which are directly affected by energy insufficiency, and promote cellular damage. A greater understanding of how inflammation affects tissue energy balance may lead to novel and effective therapeutic strategies that ultimately will benefit not only people affected by MS but also people affected by the wide range of other neurological disorders in which neuroinflammation plays an important role.
RESUMO
Quantification of blood oxygen saturation (SO2) in vivo is essential for understanding the pathogenesis of diseases in which hypoxia is thought to play a role, including inflammatory disorders such as multiple sclerosis (MS) and rheumatoid arthritis (RA). We describe a low-cost multispectral microscope and oximetry technique for calibration-free absolute oximetry of surgically exposed blood vessels in vivo. We imaged the vasculature of the dorsal spinal cord in healthy rats, and varied inspired oxygen (FiO2) in order to evaluate the sensitivity of the imaging system to changes in SO2. The venous SO2 was calculated as 67.8 ± 10.4% (average ± standard deviation), increasing to 83.1 ± 11.6% under hyperoxic conditions (100% FiO2) and returning to 67.4 ± 10.9% for a second normoxic period; the venous SO2 was 50.9 ± 15.5% and 29.2 ± 24.6% during subsequent hypoxic states (18% and 15% FiO2 respectively). We discuss the design and performance of our multispectral imaging system, and the future scope for extending this oximetry technique to quantification of hypoxia in inflamed tissue.
Assuntos
Microscopia , Oximetria/métodos , Medula Espinal/irrigação sanguínea , Medula Espinal/diagnóstico por imagem , Algoritmos , Animais , Feminino , Processamento de Imagem Assistida por Computador , Inalação , Oxigênio/sangue , Ratos , Veias/fisiologiaRESUMO
Increased activity of the sympathetic nervous system has been highlighted as a key factor that contributes to the development and maintenance of arterial hypertension. However, the factors that precipitate sustained increases in sympathetic activity remain poorly understood. Resting tissue oxygen partial pressure (PtO2) in the brainstem of anesthetized spontaneously hypertensive rats (SHRs) has been shown to be lower than in normotensive rats despite normal levels of arterial PO2. A hypoxic environment in the brainstem has been postulated to activate astroglial signalling mechanisms in the rostral ventrolateral medulla (RVLM) which in turn increase the excitability of presympathetic neuronal networks. In this study, we assessed the expression of indirect markers of tissue hypoxia and astroglial cell activation in the RVLM of SHRs and age-matched normotensive Wistar rats. Immunohistochemical labelling for hypoxia-induced factor-1α (HIF-1α) and bound pimonidazole adducts revealed the presence of tissue hypoxia in the RVLM of SHRs. Double immunostaining showed co-localization of bound pimonidazole labelling in putative presympathetic C1 neurons and in astroglial cells. Quantification of glial fibrillary acidic protein (GFAP) immunofluorescence showed relatively higher number of astrocytes and increased GFAP mean grey value density, whilst semi-quantitative analysis of skeletonized GFAP-immunoreactive processes revealed greater % area covered by astrocytic processes in the RVLM of adult SHRs. In conclusion, the morphological findings of tissue hypoxia and astrogliosis within brainstem presympathetic neuronal networks in the SHR support previous observations, showing that low brainstem PtO2 and increased astroglial signalling in the RVLM play an important role in pathological sympathoexcitation associated with the development of arterial hypertension.
Assuntos
Gliose/metabolismo , Hipóxia/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/fisiologia , Pressão Sanguínea/fisiologia , Tronco Encefálico/metabolismo , Frequência Cardíaca , Hipertensão/fisiopatologia , Masculino , Bulbo/fisiologia , Neurônios/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Sistema Nervoso Simpático/fisiopatologiaRESUMO
OBJECTIVE: Demyelination is a cardinal feature of multiple sclerosis, but it remains unclear why new lesions form, and whether they can be prevented. Neuropathological evidence suggests that demyelination can occur in the relative absence of lymphocytes, and with distinctive characteristics suggestive of a tissue energy deficit. The objective was to examine an experimental model of the early multiple sclerosis lesion and identify pathogenic mechanisms and opportunities for therapy. METHODS: Demyelinating lesions were induced in the rat spinal dorsal column by microinjection of lipopolysaccharide, and examined immunohistochemically at different stages of development. The efficacy of treatment with inspired oxygen for 2 days following lesion induction was evaluated. RESULTS: Demyelinating lesions were not centered on the injection site, but rather formed 1 week later at the white-gray matter border, preferentially including the ventral dorsal column watershed. Lesion formation was preceded by a transient early period of hypoxia and increased production of superoxide and nitric oxide. Oligodendrocyte numbers decreased at the site shortly afterward, prior to demyelination. Lesions formed at a site of inherent susceptibility to hypoxia, as revealed by exposure of naive animals to a hypoxic environment. Notably, raising the inspired oxygen (80%, normobaric) during the hypoxic period significantly reduced or prevented the demyelination. INTERPRETATION: Demyelination characteristic of at least some early multiple sclerosis lesions can arise at a vascular watershed following activation of innate immune mechanisms that provoke hypoxia, and superoxide and nitric oxide formation, all of which can compromise cellular energy sufficiency. Demyelination can be reduced or eliminated by increasing inspired oxygen to alleviate the transient hypoxia.
Assuntos
Doenças Desmielinizantes , Hipóxia , Oxigenoterapia , Medula Espinal , Animais , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/prevenção & controle , Modelos Animais de Doenças , Hipóxia/imunologia , Hipóxia/metabolismo , Hipóxia/patologia , Hipóxia/prevenção & controle , Lipopolissacarídeos , Masculino , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Esclerose Múltipla/prevenção & controle , Ratos , Ratos Sprague-Dawley , Medula Espinal/imunologia , Medula Espinal/metabolismo , Medula Espinal/patologiaRESUMO
We provide microarray data comparing genome-wide differential expression and pathology throughout life in four lines of "amyloid" transgenic mice (mutant human APP, PSEN1, or APP/PSEN1) and "TAU" transgenic mice (mutant human MAPT gene). Microarray data were validated by qPCR and by comparison to human studies, including genome-wide association study (GWAS) hits. Immune gene expression correlated tightly with plaques whereas synaptic genes correlated negatively with neurofibrillary tangles. Network analysis of immune gene modules revealed six hub genes in hippocampus of amyloid mice, four in common with cortex. The hippocampal network in TAU mice was similar except that Trem2 had hub status only in amyloid mice. The cortical network of TAU mice was entirely different with more hub genes and few in common with the other networks, suggesting reasons for specificity of cortical dysfunction in FTDP17. This Resource opens up many areas for investigation. All data are available and searchable at http://www.mouseac.org.
Assuntos
Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Placa Amiloide/genética , Proteínas tau/genética , Animais , Encéfalo/metabolismo , Demência/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Placa Amiloide/metabolismo , Proteínas tau/metabolismoRESUMO
OBJECTIVE: To explore the presence and consequences of tissue hypoxia in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). METHODS: EAE was induced in Dark Agouti rats by immunization with recombinant myelin oligodendrocyte glycoprotein and adjuvant. Tissue hypoxia was assessed in vivo using 2 independent methods: an immunohistochemical probe administered intravenously, and insertion of a physical, oxygen-sensitive probe into the spinal cord. Indirect markers of tissue hypoxia (eg, expression of hypoxia-inducible factor-1α [HIF-1α], vessel diameter, and number of vessels) were also assessed. The effects of brief (1 hour) and continued (7 days) normobaric oxygen treatment on function were evaluated in conjunction with other treatments, namely administration of a mitochondrially targeted antioxidant (MitoQ) and inhibition of inducible nitric oxide synthase (1400W). RESULTS: Observed neurological deficits were quantitatively, temporally, and spatially correlated with spinal white and gray matter hypoxia. The tissue expression of HIF-1α also correlated with loss of function. Spinal microvessels became enlarged during the hypoxic period, and their number increased at relapse. Notably, oxygen administration significantly restored function within 1 hour, with improvement persisting at least 1 week with continuous oxygen treatment. MitoQ and 1400W also caused a small but significant improvement. INTERPRETATION: We present chemical, physical, immunohistochemical, and therapeutic evidence that functional deficits caused by neuroinflammation can arise from tissue hypoxia, consistent with an energy crisis in inflamed central nervous system tissue. The neurological deficit was closely correlated with spinal white and gray matter hypoxia. This realization may indicate new avenues for therapy of neuroinflammatory diseases such as MS.
Assuntos
Encefalomielite Autoimune Experimental/fisiopatologia , Hipóxia/fisiopatologia , Inflamação/fisiopatologia , Oxigênio/farmacologia , Doenças da Medula Espinal/fisiopatologia , Amidinas/farmacologia , Animais , Benzilaminas/farmacologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Hipóxia/induzido quimicamente , Hipóxia/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Micronutrientes/farmacologia , Compostos Organofosforados/farmacologia , Oxigênio/administração & dosagem , Ratos , Recuperação de Função Fisiológica/efeitos dos fármacos , Índice de Gravidade de Doença , Método Simples-Cego , Doenças da Medula Espinal/induzido quimicamente , Doenças da Medula Espinal/tratamento farmacológico , Ubiquinona/análogos & derivados , Ubiquinona/farmacologiaRESUMO
Refractive error and accommodative responsivity were monitored at 4-month intervals over a 1-year period to determine whether an increased lag of accommodation either precedes or accompanies the development of myopia. Accommodation was measured for stimulus levels of 2.5, 3, 4, and 5 D, and both the slope of the stimulus-response function and accommodative error were computed. Almost all subjects exhibited accommodative stimulus-response gradients close to unity, although a lower gradient was observed in subjects who were myopic upon entry into the study and whose ametropia remained stable. These stable myopes also exhibited the largest lag of accommodation. These findings do not support the proposal that the development of myopia in young adults is accompanied by a reduced accommodative response during nearwork.