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A Model of Perinatal Ischemic Stroke in the Rat: 20 Years Already and What Lessons?

ABSTRACT: Neonatal hypoxia-ischemia (HI) and ischemia are a common cause of neonatal brain injury resulting in cerebral palsy with subsequent learning disabilities and epilepsy. Recent data suggest a higher incidence of focal ischemia-reperfusion located in the middle cerebral artery (MCA) territory in near-term and newborn babies. Pre-clinical studies in the field of cerebral palsy research used, and still today, the classical HI model in the P7 rat originally described by Rice et al. (1). At the end of the 90s, we designed a new model of focal ischemia in the P7 rat to explore the short and long-term pathophysiology of neonatal arterial ischemic stroke, particularly the phenomenon of reperfusion injury and its sequelae (reported in 1998). Cerebral blood-flow and cell death/damage correlates have been fully characterized. Pharmacologic manipulations have been applied to the model to test therapeutic targets. The model has proven useful for the study of seizure occurrence, a clinical hallmark for neonatal ischemia in babies. Main pre-clinical findings obtained within these 20 last years are discussed associated to clinical pattern of neonatal brain damage.

SUBMITTER: Charriaut-Marlangue C

PROVIDER: S-EPMC6090994 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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A Model of Perinatal Ischemic Stroke in the Rat: 20 Years Already and What Lessons?

Charriaut-Marlangue Christiane C Baud Olivier O

Frontiers in neurology 20180807

Neonatal hypoxia-ischemia (HI) and ischemia are a common cause of neonatal brain injury resulting in cerebral palsy with subsequent learning disabilities and epilepsy. Recent data suggest a higher incidence of focal ischemia-reperfusion located in the middle cerebral artery (MCA) territory in near-term and newborn babies. Pre-clinical studies in the field of cerebral palsy research used, and still today, the classical HI model in the P7 rat originally described by Rice et al. (1). At the end of ...[more]

PMID: 30131764

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Project description:BackgroundCanada was one of the first countries to regulate the medical use of cannabis. However, literature on Canada's medical cannabis program is limited.MethodsWe use administrative data from the medical cannabis program, and licensed cannabis vendor catalog data to describe a) the participation of patients, physicians, and cannabis vendors in the program from its inception in 1999 to 2021, and b) trends in medical cannabis consumption, prices and potency. We also use national surveys conducted over the last several decades to estimate trends in regular cannabis use (medical or otherwise) and how it changed during the medical cannabis access regimes.ResultsIn 2001, the Canadian government granted access to those with physician-documented evidence of a severe health problem that could not be managed using conventional therapies. Most patients accessed cannabis grown under a personal production license. By 2013, authorized daily cannabis dosages were very high. In 2014, the government, concerned over illegal diversion, required that cannabis be purchased from a licensed commercial grower; personal production was banned. Physicians were given responsibility for authorizing patient access. To fill the regulatory void, the physician regulatory bodies in Canada imposed their own prescribing restrictions. After these changes, the number of physicians who were willing to support patient cannabis use markedly decline but the number of patients participating in the program sharply increased. Medical cannabis use varied by province-rates were generally lower in provinces with stricter regulations on physician cannabis prescribing. Most varieties of cannabis oil available for sale are now high in CBD and low in THC. Dry cannabis varieties, conversely, tend to be high in THC and low in CBD. Inflation adjusted prices of most varieties of medical cannabis have declined over time. We find that rates of daily cannabis use (medical or otherwise) increased markedly after the 2014 policy regime. The fraction of Canadians using cannabis daily increased again after the 2018 legalization of recreational cannabis; at the same time, participation in the medical access program declined.ConclusionThe implications for patient health outcomes of changes in the medical cannabis program and legalization of recreational use remains an important area for future research.

Project description:ImportancePerinatal arterial ischemic stroke (PAIS) is a focal brain injury in term neonates that is identified postnatally but is presumed to occur near the time of birth. Many pregnancy, delivery, and fetal factors have been associated with PAIS, but early risk detection is lacking; thus, targeted treatment and prevention efforts are currently limited.ObjectiveTo develop and validate a diagnostic risk prediction model that uses common clinical factors to predict the probability of PAIS in a term neonate.Design, setting, and participantsIn this diagnostic study, a prediction model was developed using multivariable logistic regression with registry-based case data collected between January 2003, and March 2020, from the Alberta Perinatal Stroke Project, Canadian Cerebral Palsy Registry, International Pediatric Stroke Study, and Alberta Pregnancy Outcomes and Nutrition study. Criteria for inclusion were term birth and no underlying medical conditions associated with stroke diagnosis. Records with more than 20% missing data were excluded. Variable selection was based on peer-reviewed literature. Data were analyzed in September 2021.ExposuresClinical pregnancy, delivery, and neonatal factors associated with PAIS as common data elements across the 4 registries.Main outcomes and measuresThe primary outcome was the discriminative accuracy of the model predicting PAIS, measured by the concordance statistic (C statistic).ResultsOf 2571 term neonates in the initial analysis (527 [20%] case and 2044 [80%] control individuals; gestational age range, 37-42 weeks), 1389 (54%) were male, with a greater proportion of males among cases compared with controls (318 [60%] vs 1071 [52%]). The final model was developed using 1924 neonates, including 321 cases (17%) and 1603 controls (83%), and 9 clinical factors associated with risk of PAIS in term neonates: maternal age, tobacco exposure, recreational drug exposure, preeclampsia, chorioamnionitis, intrapartum maternal fever, emergency cesarean delivery, low 5-minute Apgar score, and male sex. The model demonstrated good discrimination between cases and controls (C statistic, 0.73; 95% CI, 0.69-0.76) and good model fit (Hosmer-Lemeshow P = .20). Internal validation techniques yielded similar C statistics (0.73 [95% CI, 0.69-0.77] with bootstrap resampling, 10-fold cross-validated area under the curve, 0.72 [bootstrap bias-corrected 95% CI, 0.69-0.76]), as did a sensitivity analysis using cases and controls from Alberta, Canada, only (C statistic, 0.71; 95% CI, 0.65-0.77).Conclusions and relevanceThe findings suggest that clinical variables can be used to develop and internally validate a model to predict the risk of PAIS in term neonates, with good predictive performance and strong internal validity. Identifying neonates with a high probability of PAIS who could then be screened for early diagnosis and treatment may be associated with reductions in lifelong morbidity for affected individuals and their families.

Dataset Information

A Model of Perinatal Ischemic Stroke in the Rat: 20 Years Already and What Lessons?

Publications

A Model of Perinatal Ischemic Stroke in the Rat: 20 Years Already and What Lessons?

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