Tryptophan Metabolism in Alzheimer's Disease with the Involvement of Microglia and Astrocyte Crosstalk and Gut-Brain Axis.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease characterized by extracellular Amyloid Aß peptide (Aß) deposition and intracellular Tau protein aggregation. Glia, especially microglia and astrocytes are core participants during the progression of AD and these cells are the mediators of Aß clearance and degradation. The microbiota-gut-brain axis (MGBA) is a complex interactive network between the gut and brain involved in neurodegeneration. MGBA affects the function of glia in the central nervous system (CNS), and microbial metabolites regulate the communication between astrocytes and microglia; however, whether such communication is part of AD pathophysiology remains unknown. One of the potential links in bilateral gut-brain communication is tryptophan (Trp) metabolism. The microbiota-originated Trp and its metabolites enter the CNS to control microglial activation, and the activated microglia subsequently affect astrocyte functions. The present review highlights the role of MGBA in AD pathology, especially the roles of Trp per se and its metabolism as a part of the gut microbiota and brain communications. We (i) discuss the roles of Trp derivatives in microglia-astrocyte crosstalk from a bioinformatics perspective, (ii) describe the role of glia polarization in the microglia-astrocyte crosstalk and AD pathology, and (iii) summarize the potential of Trp metabolism as a therapeutic target. Finally, we review the role of Trp in AD from the perspective of the gut-brain axis and microglia, as well as astrocyte crosstalk, to inspire the discovery of novel AD therapeutics.

Consensus definition and diagnostic criteria for neonatal encephalopathy-study protocol for a real-time modified delphi study.

BACKGROUND: 'Neonatal encephalopathy' (NE) describes a group of conditions in term infants presenting in the earliest days after birth with disturbed neurological function of cerebral origin. NE is aetiologically heterogenous; one cause is peripartum hypoxic ischaemia. Lack of uniformity in the terminology used to describe NE and its diagnostic criteria creates difficulty in the design and interpretation of research and complicates communication with families. The DEFINE study aims to use a modified Delphi approach to form a consensus definition for NE, and diagnostic criteria. METHODS: Directed by an international steering group, we will conduct a systematic review of the literature to assess the terminology used in trials of NE, and with their guidance perform an online Real-time Delphi survey to develop a consensus diagnosis and criteria for NE. A consensus meeting will be held to agree on the final terminology and criteria, and the outcome disseminated widely. DISCUSSION: A clear and consistent consensus-based definition of NE and criteria for its diagnosis, achieved by use of a modified Delphi technique, will enable more comparability of research results and improved communication among professionals and with families. IMPACT: The terms Neonatal Encephalopathy and Hypoxic Ischaemic Encephalopathy tend to be used interchangeably in the literature to describe a term newborn with signs of encephalopathy at birth. This creates difficulty in communication with families and carers, and between medical professionals and researchers, as well as creating difficulty with performance of research. The DEFINE project will use a Real-time Delphi approach to create a consensus definition for the term 'Neonatal Encephalopathy'. A definition formed by this consensus approach will be accepted and utilised by the neonatal community to improve research, outcomes, and parental experience.

Neonatal respiratory care practice among level III and IV NICUs in New England.

OBJECTIVES: To assess respiratory care guidelines and explore variations in management of very low birth weight (VLBW) infants within a collaborative care framework. Additionally, to gather clinical leaders' perspectives on guidelines and preferences for ventilation modalities. STUDY DESIGN: Leaders from each NICU participated in a practice survey regarding the prevalence of unit clinical guidelines, and management, at many stages of care. RESULTS: Units have an average of 4.3 (±2.1) guidelines, of 9 topics queried. Guideline prevalence was not associated with practice or outcomes. An FiO2 requirement of 0.3-0.4 and a CPAP of 6-7 cmH2O, are the most common thresholds for surfactant administration, which is most often done after intubation, and followed by weaning from ventilatory support. Volume targeted ventilation is commonly used. Extubation criteria vary widely. CONCLUSIONS: Results identify trends and areas of variation and suggest that the presence of guidelines alone is not predictive of outcome.

The MT1 receptor as the target of ramelteon neuroprotection in ischemic stroke.

Stroke is the leading cause of death and disability worldwide. Novel and effective therapies for ischemic stroke are urgently needed. Here, we report that melatonin receptor 1A (MT1) agonist ramelteon is a neuroprotective drug candidate as demonstrated by comprehensive experimental models of ischemic stroke, including a middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia in vivo, organotypic hippocampal slice cultures ex vivo, and cultured neurons in vitro; the neuroprotective effects of ramelteon are diminished in MT1-knockout (KO) mice and MT1-KO cultured neurons. For the first time, we report that the MT1 receptor is significantly depleted in the brain of MCAO mice, and ramelteon treatment significantly recovers the brain MT1 losses in MCAO mice, which is further explained by the Connectivity Map L1000 bioinformatic analysis that shows gene-expression signatures of MCAO mice are negatively connected to melatonin receptor agonist like Ramelteon. We demonstrate that ramelteon improves the cerebral blood flow signals in ischemic stroke that is potentially mediated, at least, partly by mechanisms of activating endothelial nitric oxide synthase. Our results also show that the neuroprotection of ramelteon counteracts reactive oxygen species-induced oxidative stress and activates the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Ramelteon inhibits the mitochondrial and autophagic death pathways in MCAO mice and cultured neurons, consistent with gene set enrichment analysis from a bioinformatics perspective angle. Our data suggest that Ramelteon is a potential neuroprotective drug candidate, and MT1 is the neuroprotective target for ischemic stroke, which provides new insights into stroke therapy. MT1-KO mice and cultured neurons may provide animal and cellular models of accelerated ischemic damage and neuronal cell death.

Molecular Toxicology and Pathophysiology of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder Associated with Traumatic Brain Injury.

The increasing comorbidity of alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) associated with traumatic brain injury (TBI) is a serious medical, economic, and social issue. However, the molecular toxicology and pathophysiological mechanisms of comorbid AUD and PTSD are not well understood and the identification of the comorbidity state markers is significantly challenging. This review summarizes the main characteristics of comorbidity between AUD and PTSD (AUD/PTSD) and highlights the significance of a comprehensive understanding of the molecular toxicology and pathophysiological mechanisms of AUD/PTSD, particularly following TBI, with a focus on the role of metabolomics, inflammation, neuroendocrine, signal transduction pathways, and genetic regulation. Instead of a separate disease state, a comprehensive examination of comorbid AUD and PTSD is emphasized by considering additive and synergistic interactions between the two diseases. Finally, we propose several hypotheses of molecular mechanisms for AUD/PTSD and discuss potential future research directions that may provide new insights and translational application opportunities.

Rates of phototherapy among ABO-incompatible newborns with a negative direct antiglobulin test.

OBJECTIVE: We analyze phototherapy rates after implementation of a Hyperbilirubinemia Clinical Pathway (HCP), which placed full-term ABOi DAT negative newborns on the low risk phototherapy nomogram, rather than medium risk, as previously done. STUDY DESIGN: A chart review was performed for ABOi newborns born ≥36 weeks gestation between January 2020 and October 2021. Primary outcome measures were rates of phototherapy across pre- and post-intervention groups and among DAT negative newborns. RESULTS: There was an increased proportion of newborns assigned to the low risk curve after the intervention. There were no significant differences in phototherapy rates among the intervention groups, although there was a non-significant decrease in phototherapy rates among DAT negative newborns after the intervention. There were no increases in adverse outcomes. CONCLUSIONS: Providers adhered to the guidelines after implementation of the HCP. ABOi DAT negative newborns can be viewed as low risk for hyperbilirubinemia requiring phototherapy.

Maternal, Infant, and Breast Milk Antibody Response Following COVID-19 Infection in Early Versus Late Gestation.

BACKGROUND: Coronavirus disease 2019 [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] infection at varying time points during the pregnancy can influence antibody levels after delivery. We aimed to examine SARS-CoV-2 IgG, IgM and IgA receptor binding domain of the spike protein and nucleocapsid protein (N-protein) reactive antibody concentrations in maternal blood, infant blood and breastmilk at birth and 6 weeks after SARS-CoV-2 infection in early versus late gestation. METHODS: Mothers with SARS-CoV-2 infection during pregnancy were enrolled between July 2020 and May 2021. Maternal blood, infant blood and breast milk samples were collected at delivery and 6 weeks postpartum. Samples were analyzed for SARS-CoV-2 spike and N-protein reactive IgG, IgM and IgA antibodies. Antibody concentrations were compared at the 2 time points and based on trimester of infection ("early" 1st/2nd vs. "late" 3rd). RESULTS: Dyads from 20 early and 11 late trimester infections were analyzed. For the entire cohort, there were no significant differences in antibody levels at delivery versus 6 weeks with the exception of breast milk levels which declined over time. Early gestation infections were associated with higher levels of breastmilk IgA to spike protein ( P = 0.04). Infant IgG levels to spike protein were higher at 6 weeks after late infections ( P = 0.04). There were strong correlations between maternal and infant IgG levels at delivery ( P < 0.01), and between breastmilk and infant IgG levels. CONCLUSIONS: SARS-CoV-2 infection in early versus late gestation leads to a persistent antibody response in maternal blood, infant blood and breast milk over the first 6 weeks after delivery.

SARS-CoV-2 in infant urine and fecal samples after in utero COVID-19 exposure.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a pandemic that has and will continue to affect many pregnant women. Knowledge regarding the risk of vertical transmission is limited. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) real-time reverse transcriptase-polymerase chain reaction (RT-PCR) of nasopharyngeal swabs typically have been used to confirm the diagnosis among infants, but whether the virus can be detected in other biological specimens, and therefore potentially transmitted in other ways, is unknown. Positive SARS-CoV-2 RT-PCR has been reported from feces and urine from adult patients. We hypothesize that the presence of SARS-CoV-2 in infant urine and fecal samples after prenatal COVID-19 exposure is low. METHODS: We examined the presence of SARS-CoV-2 RNA using RT-PCR in urine and fecal samples among 42 infants born to SARS-CoV-2-infected mothers during different stages of pregnancy. RESULTS: A urine sample was collected from 39 of 42 infants and fecal samples from all 42 infants shortly after birth. Although the majority of the women had the symptomatic disease (85.6%), we were unable to detect the presence of SARS-CoV-2 virus from any infant urine or fecal samples. CONCLUSIONS: SARS-CoV-2 was not detected in infant urine or feces after maternal infection during pregnancy, providing further evidence for low rates of perinatal transmission. IMPACT: SARS-CoV-2 was not detected in the urine or feces of infants of mothers with COVID-19 during various time points in pregnancy. This study provides further evidence for low rates of perinatal transmission of SARS-CoV-2. Results help to provide guidance on perinatal care practices for infants exposed to COVID-19 in utero.

Tartary buckwheat extract alleviates alcohol-induced acute and chronic liver injuries through the inhibition of oxidative stress and mitochondrial cell death pathway.

Alcohol use disorder (AUD) is an enormous public health problem that poses significant social, medical, and economic burdens. Under AUD, the liver is one of the most adversely affected organs. As current therapies and protective drugs for AUD-mediated liver injury are very limited, the prevention and therapy of alcoholic liver disease are urgently needed. The present study aims to investigate the beneficial effects of tartary buckwheat extract (TBE), the important component of Maopu tartary buckwheat liquor, on both alcoholic-induced acute and chronic liver injuries. We show that the TBE administration, similar to curcumin, significantly reduces the elevated serum aspartate aminotransferase and alanine aminotransferase levels, improves liver index, alleviates the elevated contents of hepatic malondialdehye, and restores the decreased contents of hepatic glutathione both in acute and chronic liver injuries in alcohol-exposed rats. Furthermore, histopathological analyses show that a medium dose of TBE (16.70 ml/kg body weight) alleviates hepatocyte morphology changes in both acute and chronic alcohol exposure models. We also show the protective effects of TBE on the cell death rates of alcohol-exposed primary cultured hepatocytes, HepG2 hepatoma, and Huh 7 hepatoma cells. Furthermore, we demonstrate that TBE exerts hepatoprotection partly through inhibiting the mitochondrial cell death pathway by reducing cytochrome c release, caspase-9 and -3 activities, and the number of TUNEL-positive cells. These effects of TBE were accompanied by enhanced levels of Bcl-2 and Bcl-xL and autophagic cell death pathway by reducing Beclin-1 expression, as well as through promoting its anti-oxidant capacity by suppressing reactive oxygen species production. This study demonstrates, for the first time, the protective effect of TBE against alcohol-induced acute and chronic liver injury in vivo and in vitro. Given the dietary nature of tartary buckwheat, pueraria, lycium barbarum, and hawthorn, the oral intake of TBE or liquor contained TBE, e.g., Maopu Tartary buckwheat liquor, compared with pure liquor consumption alone, may have the potential to alleviate alcoholic-induced liver injuries.

Improving Respiratory Support Practices to Reduce Chronic Lung Disease in Premature Infants.

INTRODUCTION: We implemented a bundle of respiratory care practices and optimized delivery of continuous positive airway pressure (CPAP) to reduce the incidence of chronic lung disease (CLD) among very low birth weight (VLBW) infants born before 33 weeks gestation. METHODS: Our multidisciplinary task force utilized 6 plan-do-study-act cycles to test our interventions. The primary outcome was the quarterly percentage of infants diagnosed with CLD; other outcomes included the percentage of infants initially managed with CPAP, intubation <72 hours of age, use of a nasal cannula, and days of ventilation, oxygen, and/or CPAP. Process measures included compliance with each of the 5 components of the bundle; balancing measures included mortality and complications of prematurity. RESULTS: Demographics were similar in the 55 infants born before and 76 infants born after the task force interventions, except for gestational age, which was lower before. CLD decreased by 55.5% (from 37.5% to 16.7%). Quarterly percentage of infants requiring intubation decreased from 87.5% to 40.8%. Quarterly average days of ventilation decreased from 11.2 to 6.1, and days of supplemental oxygen declined from 44.1 to 25.4, while the use of CPAP increased. There were no differences in adverse events including mortality, pneumothorax, use of postnatal steroids, or any retinopathy of prematurity. The incidence of patent ductus arteriosus declined from 60% to 33% (P < 0.01). CONCLUSIONS: We reduced the incidence of CLD among our very low birth weight infants born before 33 weeks gestation by over 50% without increasing any measured adverse outcomes. The incidence of patent ductus arteriosus declined.

Monogenic, Polygenic, and MicroRNA Markers for Ischemic Stroke.

Ischemic stroke (IS) is a leading disease with high mortality and disability, as well as with limited therapeutic window. Biomarkers for earlier diagnosis of IS have long been pursued. Family and twin studies confirm that genetic variations play an important role in IS pathogenesis. Besides DNA mutations found previously by genetic linkage analysis for monogenic IS (Mendelian inheritance), recent studies using genome-wide associated study (GWAS) and microRNA expression profiling have resulted in a large number of DNA and microRNA biomarkers in polygenic IS (sporadic IS), especially in different IS subtypes and imaging phenotypes. The present review summarizes genetic markers discovered by clinical studies and discusses their pathogenic molecular mechanisms involved in developmental or regenerative anomalies of blood vessel walls, neuronal apoptosis, excitotoxic death, inflammation, neurogenesis, and angiogenesis. The possible impact of environment on genetics is addressed as well. We also include a perspective on further studies and clinical application of these IS biomarkers.

Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor.

The function of melatonin as a protective agent against newborn hypoxic-ischemic (H-I) brain injury is not yet well studied, and the mechanisms by which melatonin causes neuroprotection in neurological diseases are still evolving. This study was designed to investigate whether expression of MT1 receptors is reduced in newborn H-I brain injury and whether the protective action of melatonin is by alterations of the MT1 receptors. We demonstrated that there was significant reduction in MT1 receptors in ischemic brain of mouse pups in vivo following H-I brain injury and that melatonin offers neuroprotection through upregulation of MT1 receptors. The role of MT1 receptors was further supported by observation of increased mortality in MT1 knockout mice following H-I brain injury and the reversal of the inhibitory role of melatonin on mitochondrial cell death pathways by the melatonin receptor antagonist, luzindole. These data demonstrate that melatonin mediates its neuroprotective effect in mouse models of newborn H-I brain injury, at least in part, by the restoration of MT1 receptors, the inhibition of mitochondrial cell death pathways and the suppression of astrocytic and microglial activation.

"More than Meets the Eye": When the Neonatal Course May Impact Several Years Out.

CASE: Nadia is a 7-year-old girl who you have followed since her discharge from the Neonatal Intensive Care Unit (NICU). Her parents are here today for an urgent visit with behavioral concerns, such as inattention, hyperactivity, and aggression.Nadia is a former 40-weeker born through vacuum-assisted vaginal delivery at 9 pounds 7 ounces. Her delivery was complicated with shoulder dystocia, which resulted in resuscitation. Her Apgar scores were 1, 3, and 4 at 1, 5, and 10 minutes, respectively. After intubation and stabilization on mechanical ventilation, Nadia was transferred to the NICU. Her neonatal course included systemic hypothermia using "cool cap" for hypoxic-ischemic encephalopathy (HIE) for a duration of 72 hours. She was extubated on day of life 3. She had an occupational therapy consultation for poor suck/feeding, and it quickly improved. She was discharged on day of life 14. On discharge, Nadia was referred to early intervention (EI) and the NICU follow-up clinic. Nadia was followed by EI until 12 months of age and in the NICU follow-up clinic until 18 months of age, as there were no concerns meeting her developmental milestones or her neuromotor development.At this urgent visit, Nadia's parents report that she attended a family child care from 1.5 to 3 years of age, Head Start from 3 to 5 years of age and the local public school from 5 years to present. Since starting child care, Nadia's teachers have reported that she requires a lot of redirection and refocusing, fidgets a lot in class, and can be aggressive toward her peers when unprovoked. Since her parents had not seen these behaviors at home, they thought it was a phase that she would grow out of. However, as they began to work with her to complete school assignments, they noticed that it was very difficult for Nadia to sit still and focus on work. They also struggled in the mornings to get her ready and off to school.The parents bring in Conners scales completed by themselves and her lead teacher, and with these and our clinical observations, we diagnose her with attention-deficit/hyperactivity disorder (ADHD), combined type. We discuss risk factors and ADHD management with her parents. During our discussion, Nadia's father, who has done some reading on ADHD, remembers reading an article about HIE and NICU stay being risk factors for ADHD. He wonders if this affects the choice of management of her ADHD symptoms. How would you address his query?

Neuroprotective agents for neonatal hypoxic-ischemic brain injury.

Hypoxic-ischemic (H-I) brain injury in newborns is a major cause of morbidity and mortality that claims thousands of lives each year. In this review, we summarize the promising neuroprotective agents tested on animal models and pilot clinical studies of neonatal H-I brain injury according to the different phases of the disease. These agents target various phases of injury including the early phase of excitotoxicity, oxidative stress and apoptosis as well as late-phase inflammatory reaction and neural repair. We analyze the cell survival and cell death pathways modified by these agents in neonatal H-I brain injury. We aim to 'build a bridge' between animal trials of neuroprotective agents and potential candidate treatments for future clinical applications against H-I encephalopathy.

N-acetyl-L-tryptophan delays disease onset and extends survival in an amyotrophic lateral sclerosis transgenic mouse model.

BACKGROUND: Whether L-NAT, a cytochrome c release inhibitor and an antagonist of NK-1R, provides protection in ALS is not known. RESULTS: L-NAT delays disease onset and mortality in mSOD1(G93A) ALS mice by inhibiting mitochondrial cell death pathways, inflammation, and NK-1R downregulation. CONCLUSION: L-NAT offers protection in a mouse model of ALS. SIGNIFICANCE: Data suggest the potential of L-NAT as a novel therapeutic strategy for ALS and provide insight into its action mechanisms. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, while inflammation has been implicated in its pathogenesis. Both inhibitors of cytochrome c release and antagonists of the neurokinin 1 receptor (NK-1R) have been reported to provide neuroprotection in ALS and/or other neurodegenerative diseases by us and other researchers. However, whether N-acetyl-L-tryptophan (L-NAT), an inhibitor of cytochrome c release and an antagonist of NK-1R, provides neuroprotection in ALS remains unknown. Here we demonstrate that the administration of L-NAT delayed disease onset, extended survival, and ameliorated deteriorations in motor performance in mSOD1(G93A) ALS transgenic mice. Our data showed that L-NAT reached the spinal cord, skeletal muscle, and brain. In addition, we demonstrate that L-NAT reduced the release of cytochrome c/smac/AIF, increased Bcl-xL levels, and inhibited the activation of caspase-3. L-NAT also ameliorated motor neuron loss and gross atrophy, and suppressed inflammation, as shown by decreased GFAP and Iba1 levels. Furthermore, we found gradually reduced NK-1R levels in the spinal cords of mSOD1(G93A) mice, while L-NAT treatment restored NK-1R levels. We propose the use of L-NAT as a potential therapeutic invention against ALS.

"More than meets the eye": when the neonatal course may impact several years out.

CASE: Nadia is a 7-year-old girl who you have followed since her discharge from the Neonatal Intensive Care Unit (NICU). Her parents are here today for an urgent visit with behavioral concerns, such as inattention, hyperactivity, and aggression.Nadia is a former 40-weeker born through vacuum-assisted vaginal delivery at 9 pounds 7 ounces. Her delivery was complicated with shoulder dystocia, which resulted in resuscitation. Her Apgar scores were 1, 3, and 4 at 1, 5, and 10 minutes, respectively. After intubation and stabilization on mechanical ventilation, Nadia was transferred to the NICU. Her neonatal course included systemic hypothermia using "cool cap" for hypoxic-ischemic encephalopathy (HIE) for a duration of 72 hours. She was extubated on day of life 3. She had an occupational therapy consultation for poor suck/feeding, and it quickly improved. She was discharged on day of life 14. On discharge, Nadia was referred to early intervention (EI) and the NICU follow-up clinic. Nadia was followed by EI until 12 months of age and in the NICU follow-up clinic until 18 months of age, as there were no concerns meeting her developmental milestones or her neuromotor development.At this urgent visit, Nadia's parents report that she attended a family child care from 1.5 to 3 years of age, Head Start from 3 to 5 years of age and the local public school from 5 years to present. Since starting child care, Nadia's teachers have reported that she requires a lot of redirection and refocusing, fidgets a lot in class, and can be aggressive toward her peers when unprovoked. Since her parents had not seen these behaviors at home, they thought it was a phase that she would grow out of. However, as they began to work with her to complete school assignments, they noticed that it was very difficult for Nadia to sit still and focus on work. They also struggled in the mornings to get her ready and off to school.The parents bring in Conners scales completed by themselves and her lead teacher, and with these and our clinical observations, we diagnose her with attention-deficit/hyperactivity disorder (ADHD), combined type. We discuss risk factors and ADHD management with her parents. During our discussion, Nadia's father, who has done some reading on ADHD, remembers reading an article about HIE and NICU stay being risk factors for ADHD. He wonders if this affects the choice of management of her ADHD symptoms. How would you address his query?

Emergency aortic valve replacement in systemic lupus erythematosus.

The valvular heart disease in systemic lupus erythematosus (SLE) is associated with substantial morbidity and mortality. Current therapy includes symptomatic measures and valve replacement. Overall mortality of valve replacement has been reported to be as high as 25%. Most cases of Libman-Sacks endocarditis in the literature reported dominant aortic regurgitation. We present this unusual case of a young female patient with SLE and glomerulonephritis warranting emergency isolated aortic valve replacement (AVR) for severe calcific aortic stenosis. The literature is reviewed with specific focus on the pathogenesis of and acute treatment options for this extremely rare occurrence.

Chylopericardium following atrial septal defect repair: case report.

Chylopericardium after intrapericardial cardiac operations is extremely rare. We present an unusual case of postoperative chylopericardium with cardiac tamponade following atrial septal defect repair, and we comment on the clinical course and treatment.