Echocardiography evaluation of neonatal vein of Galen aneurysmal malformation.

BACKGROUND: In neonatal vein of Galen aneurysmal malformation, vein of Galen aneurysmal malformation echocardiography remains the mainstay for early detection and explains various haemodynamic changes occurring due to a large systemic arterio-venous shunt. However, there is limited evidence of echocardiography in risk stratifying neonatal vein of Galen aneurysmal malformation vein of Galen aneurysmal malformation. The objective of this study was to identify echocardiographic parameters that could be associated with major outcomes and guide timing of neuro-intervention. METHODS: In this retrospective chart review, infants < 28 days of age with the diagnosis of vein of Galen aneurysmal malformation vein of Galen aneurysmal malformation were included. Demographic, clinical, and echocardiographic parameters were compared in neonates who survived or died with neonatal presentation. A risk algorithm model based on key echocardiographic parameters was developed to determine those who are at risk of early death. RESULTS: Of the 19 neonates included, with median birth weight 3.1 kg (IQR 2.58-3.36), nine (47%) neonates died at median age of 5 days (IQR 4-17). All neonates showed retrograde diastolic flow at the level of descending aorta by colour Doppler on the first post-natal echocardiogram at median age of 2 days (IQR 1-5.5). An aortic antegrade-to-retrograde velocity time integral ratio of < 1.5 and supra-systemic pulmonary artery pressure had 100% positive predictive value of death (p = 0.029), whereas aortic antegrade-to-retrograde velocity time integral ratio of > 1.5 and sub-systemic pulmonary artery pressure had 100% positive predictive value of survival (p = 0.029). CONCLUSION: Combination of aorta antegrade-to-retrograde velocity time integral ratio and degree of pulmonary hypertension on the first post-natal echocardiogram may help stratify the severity of disease and guide optimal timing for neuro-intervention for neonatal vein of Galen aneurysmal malformation.

Hyperglycemia and prematurity: a narrative review.

Hyperglycemia is commonly encountered in extremely preterm newborns and physiologically can be attributed to immaturity in several biochemical pathways related to glucose metabolism. Although hyperglycemia is associated with a variety of adverse outcomes frequently described in this population, evidence for causality is lacking. Variations in definitions and treatment approaches have further complicated the understanding and implications of hyperglycemia on the immediate and long-term effects in preterm newborns. In this review, we describe the relationship between hyperglycemia and organ development, outcomes, treatment options, and potential gaps in knowledge that need further research. IMPACT: Hyperglycemia is common and less well described than hypoglycemia in extremely preterm newborns. Hyperglycemia can be attributed to immaturity in several cellular pathways involved in glucose metabolism in this age group. Hyperglycemia has been shown to be associated with a variety of adverse outcomes frequently described in this population; however, evidence for causality is lacking. Variations in definitions and treatment approaches have complicated the understanding and the implications of hyperglycemia on the immediate and long-term effects outcomes. This review describes the relationship between hyperglycemia and organ development, outcomes, treatment options, and potential gaps in knowledge that need further research.

Vein of Galen aneurysmal malformation: rationalizing medical management of neonatal heart failure.

Neonates who present in high output heart failure secondary to vein of Galen aneurysmal malformation can be difficult to manage medically due to the complex physiology that results from the large shunt through the malformation. Though the cardiac function is often normal, right ventricular dilation, severe pulmonary hypertension, and systemic steal can result in inadequate organ perfusion and shock. This report recommends medical management for stabilization of neonates prior to definitive management with endovascular embolization. IMPACT: Vein of Galen aneurysmal malformation (VGAM) is a rare intracranial arteriovenous malformation, which can present in the neonatal period with high output heart failure. Heart failure secondary to VGAM is often difficult to manage and is associated with high mortality and morbidity. Despite optimal medical management, many patients require urgent endovascular embolization for stabilization of their heart failure. This report offers discrete recommendations that can be used by clinicians as guidelines for the medical management of heart failure in newborns with VGAM.

Nitric oxide and the brain. Part 1: Mechanisms of regulation, transport and effects on the developing brain.

Apart from its known actions as a pulmonary vasodilator, nitric oxide (NO) is a key signal mediator in the neonatal brain. Despite the extensive use of NO for pulmonary artery hypertension (PAH), its actions in the setting of brain hypoxia and ischemia, which co-exists with PAH in 20-30% of affected infants, are not well established. This review focuses on the mechanisms of actions of NO covering the basic, translational, and clinical evidence of its neuroprotective and neurotoxic properties. In this first part, we present the physiology of transport and delivery of NO to the brain and the regulation of cerebrovascular and systemic circulation by NO, as well the role of NO in the development of the immature brain. IMPACT: NO can be transferred from the site of production to the site of action rapidly and affects the central nervous system. Inhaled NO (iNO), a commonly used medication, can have significant effects on the neonatal brain. NO regulates the cerebrovascular and systemic circulation and plays a role in the development of the immature brain. This review describes the properties of NO under physiologic conditions and under stress. The impact of this review is that it describes the effects of NO, especially regarding the vulnerable neonatal brain, and helps understand the conditions that could contribute to neurotoxicity or neuroprotection.

Nitric oxide and the brain. Part 2: Effects following neonatal brain injury-friend or foe?

Nitric oxide (NO) has critical roles in a wide variety of key biologic functions and has intricate transport mechanisms for delivery to key distal tissues under normal conditions. However, NO also plays important roles during disease processes, such as hypoxia-ischemia, asphyxia, neuro-inflammation, and retinopathy of prematurity. The effects of exogenous NO on the developing neonatal brain remain controversial. Inhaled NO (iNO) can be neuroprotective or toxic depending on a variety of factors, including cellular redox state, underlying disease processes, duration of treatment, and dose. This review identifies key gaps in knowledge that should prompt further investigation into the possible role of iNO as a therapeutic agent after injury to the brain. IMPACT: NO is a key signal mediator in the neonatal brain with neuroprotective and neurotoxic properties. iNO, a commonly used medication, has significant effects on the neonatal brain. Dosing, duration, and timing of administration of iNO can affect the developing brain. This review article summarizes the roles of NO in association with various disease processes that impact neonates, such as brain hypoxia-ischemia, asphyxia, retinopathy of prematurity, and neuroinflammation. The impact of this review is that it clearly describes gaps in knowledge, and makes the case for further, targeted studies in each of the identified areas.

Effects of Src Kinase Inhibition on Expression of Protein Tyrosine Phosphatase 1B after Brain Hypoxia in a Piglet Animal Model.

BACKGROUND: Protein tyrosine phosphatases (PTPs) in conjunction with protein tyrosine kinases (PTKs) regulate cellular processes by posttranslational modifications of signal transduction proteins. PTP nonreceptor type 1B (PTP-1B) is an enzyme of the PTP family. We have previously shown that hypoxia induces an increase in activation of a class of nonreceptor PTK, the Src kinases. In the present study, we investigated the changes that occur in the expression of PTP-1B in the cytosolic component of the brain of newborn piglets acutely after hypoxia as well as long term for up to 2 weeks. METHODS: Newborn piglets were divided into groups: normoxia, hypoxia, hypoxia followed by 1 day and 15 days in FiO2 0.21, and hypoxia pretreated with Src kinase inhibitor PP2, prior to hypoxia followed by 1 day and 15 days. Hypoxia was achieved by providing 7% FiO2 for 1 hour and PTP-1B expression was measured via immunoblotting. RESULTS: PTP-1B increased posthypoxia by about 30% and persisted for 2 weeks while Src kinase inhibition attenuated the expected PTP-1B-increased expression. CONCLUSIONS: Our study suggests that Src kinase mediates a hypoxia-induced increased PTP-1B expression.

Temporal Changes in Caspase-1 and Caspase-8 Activities Following Brain Hypoxia With and Without Src kinase Inhibition in a Piglet Animal Model.

The Src family kinases are a family of intracellular, non-receptor tyrosine kinases that are involved in a variety of cellular functions including the regulation of inflammation and apoptosis after brain hypoxia. Caspase-1 (C1) activates IL-1ß through the formation of complex structures, the inflammasomes, while caspase-8 (C8) is part of the extrinsic apoptotic pathway. C8 has been found to directly activate the production of IL-1ß. Previously, we observed that C1 and IL-1ß are increased in the acute phase after hypoxia in the brain of piglets, but they follow a different pattern long term, with C1 remaining activated throughout the period of observation, while IL-1ß returning to baseline at 15 days. Src kinase inhibition ameliorated the activation of C1 and IL-1ß early, but did not appear to have any effect long term. Prompted by these findings, we assessed the changes that occur over time (1 h and 15 days) in C1 and C8 activities after brain hypoxia as well as the effect of pretreatment with a Src kinase inhibitor, PP2 on these biochemical markers. Enzymatic activities were determined by spectrophotometry with measurements of C1 and C8 in each cytosolic brain sample (N = 4 in each group). We found that C1 and C8 activities increase in the acute phase following hypoxia in the brain of newborn piglets, with C8 relatively more than C1 (C8/C1 ratio increased from 2:1 as baseline to 3:1 in hypoxia). Fifteen days after hypoxia C8/C1 ratio decreased to about 1:1. In piglets that were pretreated with a Src kinase selective inhibitor (PP2) and then subjected to hypoxia, the C8/C1 ratio early increase was not observed. Immediately after hypoxia C8 and C1 follow a similar pattern of increase while long term this appears to dissociate. We propose that following this experimental methodology, the previously observed IL-1ß production after hypoxia might be associated with C8 rather than C1 and that Src kinase is involved in the above process.

The role of SRC kinase in the caspase-1 pathway after hypoxia in the brain of newborn piglets.

Hypoxia induces a cerebral inflammatory response, which contributes to brain injury. Inflammasomes are complex intracellular molecular structures that initiate the inflammatory cascade. Caspase-1 and interleukin 1-ß (IL-1ß), have been established as markers of inflammasome activation. Src kinase, a cytosolic non-receptor protein tyrosine kinase, is linked to cell proliferation and differentiation and is up regulated during hypoxia. The role of Src kinase in the above pathway is not fully understood. The present study tests the hypothesis that inhibition of Src kinase, by a selective inhibitor, PP2, will prevent the activation of caspase-1 and production of IL-1ß acutely, as well as at 1 and 15 days after hypoxia in the cerebral cortex of the newborn piglet. Piglets were divided into: Normoxia (Nx), Hypoxia acute (Hx), Hypoxia-day 1 (Hx-day 1), and Hypoxia day 15 (Hx-day 15). Piglets pretreated with Src kinase inhibitor, PP2, 1 mg/kg IV, 30 min prior to hypoxia were divided into: Hypoxia acute (Hx + PP2), 1 day (Hx + PP2-day 1), and day 15 (Hx + PP2-day 15). Hypoxia was induced by exposing the piglets to an FiO2 of 0.07 for 1 hour. Caspase-1 activity and expression were determined with spectrophotometry and Western blot respectively, while IL-1ß levels were measured by solid phase ELISA. Caspase-1 activation was achieved immediately (within 1 h) after hypoxia and persisted for 15 days. IL-1ß level was also increased after hypoxia reaching a maximum level at 24 h following hypoxia and returned to baseline by 15 days. Administration of PP2 attenuated the activity acutely, but not the expression of the caspase-1. IL-1ß level at 24 h after hypoxia returned to baseline in piglets that were pretreated with PP2. We provide evidence that inhibition of Src kinase in the acute phase after hypoxia involves changes in the production or processing of caspase-1 subunits. Our data suggest that Src kinase mediates hypoxia-induced caspase-1 activation in the cerebral cortex of newborn piglets. Inhibition of Src kinase may attenuate the neuroinflammatory response and could represent a potential target for neuroprotection after hypoxic injury.

Reassessing the transport properties of fluids: A symbolic regression approach.

The viscosity and thermal conductivity coefficients of the Lennard-Jones fluid are extracted through symbolic regression (SR) techniques from data derived from simulations at the atomic scale. This data-oriented approach provides closed form relations that achieve fine accuracy when compared to well-established theoretical, empirical, or approximate equations, fully transparent, with small complexity and high interpretability. The novelty is further outlined by suggesting analytical expressions for estimating fluid transport properties across the whole phase space, from a dilute gas to a dense liquid, by considering only two macroscopic properties (density and temperature). In such expressions, the underlying physical mechanisms are reflected, while, at the same time, it can be a computationally efficient alternative to costly in time and size first principle and/or molecular dynamics simulations.

Implementation of morbidity and mortality conference in a community hospital NICU and narrative review.

Background: The process of morbidity and mortality review (MMR) is recognized as an essential component of quality improvement, patient safety, attitudes towards patient safety, and continuing education. Despite the common use of MMR for all disciplines of medical care, recommendations have not been published regarding the implementation of MMR in a community hospital setting in the United States. Objectives: Review the literature on MMR conferences. Describe the implementation of an MMR conference in a community hospital neonatal intensive care unit (NICU). Conclusions: The establishment of a case overview method of MMR is feasible for a community hospital NICU. It increases staff and physician group awareness and education over common and complex mortality and morbidity etiologies, improves staff participation with unit management, links case presentation with open discussion and action items, and identifies opportunities for systemic changes to improve patient care.

Fluid Properties Extraction in Confined Nanochannels with Molecular Dynamics and Symbolic Regression Methods.

In this paper, we propose an alternative road to calculate the transport coefficients of fluids and the slip length inside nano-conduits in a Poiseuille-like geometry. These are all computationally demanding properties that depend on dynamic, thermal, and geometrical characteristics of the implied fluid and the wall material. By introducing the genetic programming-based method of symbolic regression, we are able to derive interpretable data-based mathematical expressions based on previous molecular dynamics simulation data. Emphasis is placed on the physical interpretability of the symbolic expressions. The outcome is a set of mathematical equations, with reduced complexity and increased accuracy, that adhere to existing domain knowledge and can be exploited in fluid property interpolation and extrapolation, bypassing timely simulations when possible.

Artificial Intelligence in Physical Sciences: Symbolic Regression Trends and Perspectives.

Symbolic regression (SR) is a machine learning-based regression method based on genetic programming principles that integrates techniques and processes from heterogeneous scientific fields and is capable of providing analytical equations purely from data. This remarkable characteristic diminishes the need to incorporate prior knowledge about the investigated system. SR can spot profound and elucidate ambiguous relations that can be generalizable, applicable, explainable and span over most scientific, technological, economical, and social principles. In this review, current state of the art is documented, technical and physical characteristics of SR are presented, the available programming techniques are investigated, fields of application are explored, and future perspectives are discussed. Supplementary Information: The online version contains supplementary material available at 10.1007/s11831-023-09922-z.

An oncogenic isoform of septin 9 promotes the formation of juxtanuclear invadopodia by reducing nuclear deformability.

Invadopodia are extracellular matrix (ECM) degrading structures, which promote cancer cell invasion. The nucleus is increasingly viewed as a mechanosensory organelle that determines migratory strategies. However, how the nucleus crosstalks with invadopodia is little known. Here, we report that the oncogenic septin 9 isoform 1 (SEPT9_i1) is a component of breast cancer invadopodia. SEPT9_i1 depletion diminishes invadopodia formation and the clustering of invadopodia precursor components TKS5 and cortactin. This phenotype is characterized by deformed nuclei, and nuclear envelopes with folds and grooves. We show that SEPT9_i1 localizes to the nuclear envelope and juxtanuclear invadopodia. Moreover, exogenous lamin A rescues nuclear morphology and juxtanuclear TKS5 clusters. Importantly, SEPT9_i1 is required for the amplification of juxtanuclear invadopodia, which is induced by the epidermal growth factor. We posit that nuclei of low deformability favor the formation of juxtanuclear invadopodia in a SEPT9_i1-dependent manner, which functions as a tunable mechanism for overcoming ECM impenetrability. Highlights: The oncogenic SEPT9_i1 is enriched in breast cancer invadopodia in 2D and 3D ECMSEPT9_i1 promotes invadopodia precursor clustering and invadopodia elongationSEPT9_i1 localizes to the nuclear envelope and reduces nuclear deformabilitySEPT9_i1 is required for EGF-induced amplification of juxtanuclear invadopodia. eTOC Blurb: Invadopodia promote the invasion of metastatic cancers. The nucleus is a mechanosensory organelle that determines migratory strategies, but how it crosstalks with invadopodia is unknown. Okletey et al show that the oncogenic isoform SEPT9_i1 promotes nuclear envelope stability and the formation of invadopodia at juxtanuclear areas of the plasma membrane.

An oncogenic isoform of septin 9 promotes the formation of juxtanuclear invadopodia by reducing nuclear deformability.

Invadopodia are extracellular matrix (ECM) degrading structures, which promote cancer cell invasion. The nucleus is increasingly viewed as a mechanosensory organelle that determines migratory strategies. However, how the nucleus crosstalks with invadopodia is little known. Here, we report that the oncogenic septin 9 isoform 1 (SEPT9_i1) is a component of breast cancer invadopodia. SEPT9_i1 depletion diminishes invadopodium formation and the clustering of the invadopodium precursor components TKS5 and cortactin. This phenotype is characterized by deformed nuclei and nuclear envelopes with folds and grooves. We show that SEPT9_i1 localizes to the nuclear envelope and juxtanuclear invadopodia. Moreover, exogenous lamin A rescues nuclear morphology and juxtanuclear TKS5 clusters. Importantly, SEPT9_i1 is required for the amplification of juxtanuclear invadopodia, which is induced by the epidermal growth factor. We posit that nuclei of low deformability favor the formation of juxtanuclear invadopodia in a SEPT9_i1-dependent manner, which functions as a tunable mechanism for overcoming ECM impenetrability.

From Takotsubo to Yamaguchi.

Our patient was a 56-year-old Caucasian female who had 34 emergency department visits to our center with recurrent chest pain, of which eleven were of cardiac etiology, involving cardiac causes over the period of seven years. Her chest pain was diagnosed as atypical during her previous visits. Chest CT revealed "ace-of-spades" in the cardiac transverse section. A transthoracic echocardiogram (TTE) demonstrated apical hypertrophy with end-systolic cavity obliteration and an ejection fraction (EF) of 65%-70%, seated amidst a normal-sized left ventricle, with normal wall thickness, indicating Yamaguchi syndrome. In the case report, we portray the need to widen the spectrum of differentials in an encounter with a patient presenting with chest pain.

Critical Stenosis in Left Anterior Descending Artery: Beware of T- Wave Inversions.

Wellens' syndrome (WS) is a pattern on an electrocardiogram (ECG) characterized by biphasic T waves or deeply inverted T waves in leads V2-V3 with a recent clinical history of angina. Wellens' pattern on the ECG is particular for critical left anterior descending artery (LAD) stenosis. Wellens' sign and WS have been used interchangeably in the literature. However, the typical patterns of ECG changes noted are mostly represented by Wellens' sign. These ECG changes have been crucial in identifying this subset of patients with severe LAD disease.

Developmental changes of the fetal and neonatal thyroid gland and functional consequences on the cardiovascular system.

Thyroid hormones play an important role in the development and function of the cardiac myocyte. Dysregulation of the thyroid hormone milieu affects the fetal cardiac cells via complex molecular mechanisms, either by altering gene expression or directly by affecting post-translational processes. This review offers a comprehensive summary of the effects of thyroid hormones on the developing cardiovascular system and its adaptation. Furthermore, we will highlight the gaps in knowledge and provide suggestions for future research.

Human Plasma In-Cell Western Assays-An In vitro Predictor for In vivo Pharmacology in Oncology Drug Discovery.

Evaluation of in vivo potencies plays an important role in drug discovery. Traditionally, the cellular activity and percent of plasma protein binding of a test agent are evaluated separately, with the plasma protein binding-adjusted cellular potency computation used to estimate in vivo potency. This process is costly, takes weeks to complete, and is increasingly unreliable for compounds that bind extensively to plasma proteins. Described in this article is a simple, high-throughput human plasma in-cell Western (ICW) assay that directly incorporates plasma protein binding into a cellular pharmacodynamic assay to provide a rapid and accurate estimate of in vivo potencies. The assay is versatile and can be readily employed for various targets that require short treatment periods for displaying maximal biological responses. © 2021 Wiley Periodicals LLC. Basic Protocol: Concentration-dependent human plasma ICW assay to determine test compound IC50 against the target of interest.

Cerebral Blood Flow Monitoring in High-Risk Fetal and Neonatal Populations.

Cerebrovascular pressure autoregulation promotes stable cerebral blood flow (CBF) across a range of arterial blood pressures. Cerebral autoregulation (CA) is a developmental process that reaches maturity around term gestation and can be monitored prenatally with both Doppler ultrasound and magnetic resonance imaging (MRI) techniques. Postnatally, there are key advantages and limitations to assessing CA with Doppler ultrasound, MRI, and near-infrared spectroscopy. Here we review these CBF monitoring techniques as well as their application to both fetal and neonatal populations at risk of perturbations in CBF. Specifically, we discuss CBF monitoring in fetuses with intrauterine growth restriction, anemia, congenital heart disease, neonates born preterm and those with hypoxic-ischemic encephalopathy. We conclude the review with insights into the future directions in this field with an emphasis on collaborative science and precision medicine approaches.

Sgarbossa criteria and acute myocardial infarction.

Diagnosis of acute ST-elevation myocardial infarction in the presence of left bundle branch block is difficult. present a case of acute myocardial infarction with LBBB diagnosed and treated using the Sgarbossa criteria.