Faculty Opinions recommendation of A critical time window for dopamine actions on the structural plasticity of dendritic spines.

SUMMARYExperience-dependent refinement of neuronal connections is critically important for brain development and learning. Here we show that ion flow-independent NMDAR signaling is required for the long-term dendritic spine growth that is a vital component of brain circuit plasticity. We found that inhibition of p38 MAPK, shown to be downstream of non-ionotropic NMDAR signaling in LTD and spine shrinkage, blocked LTP-induced spine growth but not LTP. We hypothesized that non-ionotropic NMDAR signaling drives the cytoskeletal changes that support bidirectional spine structural plasticity. Indeed, we found that key signaling components downstream of non-ionotropic NMDAR function in LTD-induced spine shrinkage also are necessary for LTP-induced spine growth. Furthermore, NMDAR conformational signaling with coincident Ca2+ influx is sufficient to drive CaMKII-dependent long-term spine growth, even when Ca2+ is artificially driven through voltage-gated Ca2+ channels. Our results support a model in which non-ionotropic NMDAR signaling gates the bidirectional spine structural changes vital for brain plasticity.

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Time-Varying Associations Between an Exposure History and a Subsequent Health Outcome: A landmark Approach to Identify Critical Windows.

10.21203/rs.3.rs-322375/v1 ◽

2021 ◽

Author(s):

Maude Wagner ◽

Francine Grodstein ◽

Karen Leffondre ◽

Cécilia Samieri ◽

Cécile Proust-Lima

Keyword(s):

Risk Factors ◽

Health Outcome ◽

Measurement Errors ◽

Mixed Model ◽

Time Window ◽

Time Windows ◽

Critical Time ◽

Cumulative Exposure ◽

Exposure Measurement ◽

Exposure History

Abstract Background: Long-term behavioral and health risk factors constitute a primary focus of research on the etiology of chronic diseases. Yet, identifying critical time-windows during which risk factors have the strongest impact on disease risk is challenging. To assess the trajectory of association of an exposure history with an outcome, the weighted cumulative exposure index (WCIE) has been proposed, with weights reﬂecting the relative importance of exposures at diﬀerent times. However, WCIE is restricted to a complete observed error-free exposure whereas exposures are often measured with intermittent missingness and error. Moreover, it rarely explores exposure history that is very distant from the outcome as usually sought in life-course epidemiology.Methods: We extend the WCIE methodology to (i) exposures that are intermittently measured with error, and (ii) contexts where the exposure time-window precedes the outcome time-window using a landmark approach. First, the individual exposure history up to the landmark time is estimated using a mixed model that handles missing data and error in exposure measurement, and the predicted complete error-free exposure history is derived. Then the WCIE methodology is applied to assess the trajectory of association between the predicted exposure history and the health outcome collected after the landmark time. In our context, the health outcome is a longitudinal marker analyzed using a mixed model.Results: A simulation study ﬁrst demonstrates the correct inference obtained with this approach. Then, applied to the Nurses’ Health Study (19,415 women) to investigate the association between body mass index history (collected from midlife) and subsequent cognitive decline (evaluated after age 70), the method identiﬁed two major critical windows of association: long before the ﬁrst cognitive evaluation (roughly 24 to 12 years), higher levels of BMI were associated with poorer cognition. In contrast, adjusted for the whole history, higher levels of BMI became associated with better cognition in the last years prior to the ﬁrst cognitive interview, thus reﬂecting reverse causation (changes in exposure due to underlying disease).Conclusions: This approach, easy to implement, provides a ﬂexible tool for studying complex dynamic relationships and identifying critical time windows while accounting for exposure measurement errors.

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Clinical Evaluation of Herbal Medicine (ICH-012) in Treating Acute Cerebral Haemorrhage: Safety and Efficacy from 6- to 72-Hour Time Window (CRRICHTrial-II)

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/3120179 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Qixin Zhang ◽

Liling Zeng ◽

Xiuyan Chen ◽

Yuexiang Zhou ◽

Baoying Gong ◽

...

Keyword(s):

Herbal Medicine ◽

Ct Scan ◽

Time Window ◽

Rapid Change ◽

Herbal Medicines ◽

Critical Time ◽

Cerebral Haemorrhage ◽

High Morbidity ◽

Safety And Efficacy ◽

Link Type

Background. Hypertensive intracerebral haemorrhage (HICH), which is characterized by rapid change, high morbidity, and mortality, is extremely dangerous. Both medical and surgical treatments lack definitive evidence and remain controversial. A prospective RCT that we have conducted has shown that the usage of the herbal medicine ICH-012 within 6 h of the event may increase the risk of haematoma enlargement and gastrointestinal bleeding. However, the volume of haematoma remains stable after 6 h. Thus, we will increase the time window to the period from 6 to 72 h after onset to evaluate the safety and efficacy of ICH-012 treating ICH (ClinicalTrial.gov ID: NCT03354026). Methods/Design. The CRRICHTrial-II study, a prospective, double-blinded, controlled, multicentre RCT, includes three groups: A, B, and C. Group A patients were treated with 8 herbal medicines (with 2 herbal medicines of Hirudo and Tabanus as well as 6 other combined herbal medicines of Group B) and Group C were placebo. Patients should meet all the inclusion criteria: age between 18 and 80 and diagnosis of HICH by brain CT scan between 6 and 72 h from the onset. The CT scan will be taken at four critical time points: baseline, between 6 and 72h, 24h after onset, and between 10 and 14 days after onset. The drug intervention lasts 10 days, and there is a follow-up visit taken after 90 days. The haematoma enlargement after 24 h onset as demonstrated by CT is the primary outcome. Discussion. A large amount of data from high-quality RCTs is needed for the extensive clinical application of herbal medicine. The CRRICHTrial-II will evaluate the safety and effectiveness of ICH-012 in a safer time window between 6 and 72 h and investigate the possible mechanisms of action and direction of herbal medicine in the haematoma growth after HICH. Trial registration at ClinicalTrial.gov, ID: NCT03354026, is registered on 23rd Nov. 2017.

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