A narrative review on treatment strategies for neonatal hypoxic ischemic encephalopathy.

Background and Objective: Hypoxic-ischemic encephalopathy (HIE) is a leading cause of death and disability worldwide. Therapeutic hypothermia (TH) represents a significant achievement in the translation of scientific research to clinical application, but it is currently the only neuroprotective treatment for HIE. This review aims to revisit the use of TH for HIE and its longitudinal impact on patient outcomes to readers new to the field of HIE. We discuss how emerging therapies address the broader pathophysiology of injury progression in the neonatal brain days to years after HIE. Methods: We included full articles and book chapters published in English on PubMed with references to "hypoxic ischemic encephalopathy", "birth asphyxia", "therapeutic hypothermia", or "neonatal encephalopathy". We limited our review to outcomes on term infants and to new therapeutics that are in the second phase of clinical trials. Key Content and Findings: Despite the use of TH for HIE, mortality remains high. Analysis of longitudinal studies reveals a high incidence of ongoing disability even with the implementation of TH. New therapeutics addressing the secondary phase and the less understood tertiary phase of brain injury are in clinical trials as adjunctive treatments to TH to support additional neurological repair and regeneration. Conclusions: TH successfully improves outcomes after HIE, and it continues to be optimized. Larger studies are needed to understand its use in mild cases of HIE and if certain factors, such as sex, affect long term outcomes. TH primarily acts in the initial phases of injury, while new pharmaceutical therapies target additional injury pathways into the tertiary phases of injury. This may allow for more effective approaches to treatment and improvement of long-term functional outcomes after HIE.

CD11bhigh B Cells Increase after Stroke and Regulate Microglia.

Recent studies have highlighted the deleterious contributions of B cells to post-stroke recovery and cognitive decline. Different B cell subsets have been proposed on the basis of expression levels of transcription factors (e.g., T-bet) as well as specific surface proteins. CD11b (α-chain of integrin) is expressed by several immune cell types and is involved in regulation of cell motility, phagocytosis, and other essential functions of host immunity. Although B cells express CD11b, the CD11bhigh subset of B cells has not been well characterized, especially in immune dysregulation seen with aging and after stroke. Here, we investigate the role of CD11bhigh B cells in immune responses after stroke in young and aged mice. We evaluated the ability of CD11bhigh B cells to influence pro- and anti-inflammatory phenotypes of young and aged microglia (MG). We hypothesized that CD11bhigh B cells accumulate in the brain and contribute to neuroinflammation in aging and after stroke. We found that CD11bhigh B cells are a heterogeneous subpopulation of B cells predominantly present in naive aged mice. Their frequency increases in the brain after stroke in young and aged mice. Importantly, CD11bhigh B cells regulate MG phenotype and increase MG phagocytosis in both ex vivo and in vivo settings, likely by production of regulatory cytokines (e.g., TNF-α). As both APCs and adaptive immune cells with long-term memory function, B cells are uniquely positioned to regulate acute and chronic phases of the post-stroke immune response, and their influence is subset specific.

Gut dysbiosis and age-related neurological diseases in females.

Historically, females have been underrepresented in biological research. With increased interest in the gut microbiome and the gut-brain axis, it is important for researchers to pursue studies that consider sex as a biological variable. The composition of the gut microbiome is influenced by environmental factors, disease, diet, and varies with age and by sex. Detrimental changes in the gut microbiome, referred to as dysbiosis, is believed to influence the development and progression of age-related neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and stroke. Many are investigating the changes in microbial populations in order or to better understand the role of the gut immunity and the microbiome in neurodegenerative diseases, many of which the exact etiology remains elusive, and no cures exist.  Others are working to find diagnostic markers for earlier detection, or to therapeutically modulate microbial populations using probiotics. However, while all these diseases present in reproductively senescent females, most studies only use male animals for their experimental design. Reproductively senescent females have been shown to have differences in disease progression, inflammatory responses, and microbiota composition, therefore, for research to be translational to affected populations it is necessary for appropriate models to be used. This review discusses factors that influence the gut microbiome and the gut brain axis in females, and highlights studies that have investigated the role of dysbiosis in age-related neurodegenerative disorders that have included females in their study design.