Does the distal ureteral diameter ratio (UDR) matter in the surgical management of vesicoureteral reflux in children?

PURPOSE: To evaluate UDR reliability, sensitivity, specificity and to identify the best treatment basing on UDR among single or double endoscopic injections and ureteral reimplantation. METHODS: Data of patients affected by primary VUR and treated by endoscopic injection over a 10 years period were retrospectively analyzed. Two radiologist attributed reflux grade and UDR on voiding cystourethrogram twice and blinded. Follow-up focused on resolution after 1 or 2 endoscopic injections. Relation between UDR, reflux grade and outcomes were analyzed. RESULTS: Patient enrolled were 198. Low grade VUR was present in 24.8%, grade 3 in 41.6%, grade 4-5 in 33.6%. Resolution after one injection was obtained in 88 patients; among 110 not resolved 104 cases had a second injection. Success after 2 injections was reported in 138 cases. UDR showed a higher reliability compared with reflux grade both in intra than inter-reader measurement (ICC > 90%). Success after 1 or 2 injections was reported for UDR < 0.33 and UDR < 0.47 respectively. CONCLUSION: UDR shows to be a more reliable measurement that allows for an objective estimation of VUR severity and prognosis. It represents a quantitative parameter that might be useful to identify patients who may benefit endoscopic or surgical treatment, avoiding unnecessary under or over-treatment.

Redox Imbalance in Neurological Disorders in Adults and Children.

Oxygen is a central molecule for numerous metabolic and cytophysiological processes, and, indeed, its imbalance can lead to numerous pathological consequences. In the human body, the brain is an aerobic organ and for this reason, it is very sensitive to oxygen equilibrium. The consequences of oxygen imbalance are especially devastating when occurring in this organ. Indeed, oxygen imbalance can lead to hypoxia, hyperoxia, protein misfolding, mitochondria dysfunction, alterations in heme metabolism and neuroinflammation. Consequently, these dysfunctions can cause numerous neurological alterations, both in the pediatric life and in the adult ages. These disorders share numerous common pathways, most of which are consequent to redox imbalance. In this review, we will focus on the dysfunctions present in neurodegenerative disorders (specifically Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis) and pediatric neurological disorders (X-adrenoleukodystrophies, spinal muscular atrophy, mucopolysaccharidoses and Pelizaeus-Merzbacher Disease), highlighting their underlining dysfunction in redox and identifying potential therapeutic strategies.

The Oxygen Cascade from Atmosphere to Mitochondria as a Tool to Understand the (Mal)adaptation to Hypoxia.

Hypoxia is a life-threatening challenge for about 1% of the world population, as well as a contributor to high morbidity and mortality scores in patients affected by various cardiopulmonary, hematological, and circulatory diseases. However, the adaptation to hypoxia represents a failure for a relevant portion of the cases as the pathways of potential adaptation often conflict with well-being and generate diseases that in certain areas of the world still afflict up to one-third of the populations living at altitude. To help understand the mechanisms of adaptation and maladaptation, this review examines the various steps of the oxygen cascade from the atmosphere to the mitochondria distinguishing the patterns related to physiological (i.e., due to altitude) and pathological (i.e., due to a pre-existing disease) hypoxia. The aim is to assess the ability of humans to adapt to hypoxia in a multidisciplinary approach that correlates the function of genes, molecules, and cells with the physiologic and pathological outcomes. We conclude that, in most cases, it is not hypoxia by itself that generates diseases, but rather the attempts to adapt to the hypoxia condition. This underlies the paradigm shift that when adaptation to hypoxia becomes excessive, it translates into maladaptation.

Enhanced-Precision Measurement of Glutathionyl Hemoglobin by MALDI-ToF MS.

Glutathionyl-hemoglobin (HbSSG) is used as a human biomarker to pinpoint systemic oxidative stress caused by various pathological conditions, noxious lifestyles, and exposure to drugs and environmental or workplace toxicants. Measurement by MALDI mass spectrometry is most frequently used, however, the method suffers from excessive uncontrolled variability. This article describes the improvement of a MALDI-ToF mass spectrometry method for HbSSG measurement through enhanced precision, based on strict control of sample preparation steps and spreadsheet-based data analysis. This improved method displays enhanced precision in the analysis of several hundred samples deriving from studies in different classes of healthy and diseased human subjects. Levels span from 0.5% (lower limit of detection) up to 30%, measured with a precision (as SE%) < 0.5%. We optimized this global procedure to improve data quality and to enable the Operator to work with a reduced physical and psychological strain. Application of this method, for which full instruction and the data analysis spreadsheet are supplied, can encourage the exploitation of HbSSG to study human oxidative stress in a variety of pathological and living conditions and to rationally test the efficacy of antioxidant measures and treatments in the frame of health promotion.

Oxygen Sensing in Neurodegenerative Diseases: Current Mechanisms, Implication of Transcriptional Response, and Pharmacological Modulation.

Significance: Oxygen (O2) sensing is the fundamental process through which organisms respond to changes in O2 levels. Complex networks exist allowing the maintenance of O2 levels through the perception, capture, binding, transport, and delivery of molecular O2. The brain extreme sensitivity to O2 balance makes the dysregulation of related processes crucial players in the pathogenesis of neurodegenerative diseases (NDs). In this study, we wish to review the most relevant advances in O2 sensing in relation to Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Recent Advances: Over the years, it has been clarified that most NDs share common pathways, a great number of which are in relation to O2 imbalance. These include hypoxia, hyperoxia, reactive oxygen species production, metabolism of metals, protein misfolding, and neuroinflammation. Critical Issues: There is still a gap in knowledge concerning how O2 sensing plays a role in the above indicated neurodegenerations. Specifically, O2 concentrations are perceived in body sites that are not limited to the brain, but primarily reside in other organs. Moreover, the mechanisms of O2 sensing, gene expression, and signal transduction seem to correlate with neurodegeneration, but many aspects are mechanistically still unexplained. Future Directions: Future studies should focus on the precise characterization of O2 level disruption and O2 sensing mechanisms in NDs. Moreover, advances need to be made also concerning the techniques used to assess O2 sensing dysfunctions in these diseases. There is also the need to develop innovative therapies targeting this precise mechanism rather than its secondary effects, as early intervention is necessary. Antioxid. Redox Signal. 38, 160-182.

Janus, or the Inevitable Battle Between Too Much and Too Little Oxygen.

Significance: Oxygen levels are key regulators of virtually every living mammalian cell, under both physiological and pathological conditions. Starting from embryonic and fetal development, through the growth, onset, and progression of diseases, oxygen is a subtle, although pivotal, mediator of key processes such as differentiation, proliferation, autophagy, necrosis, and apoptosis. Hypoxia-driven modifications of cellular physiology are investigated in depth or for their clinical and translational relevance, especially in the ischemic scenario. Recent Advances: The mild or severe lack of oxygen is, undoubtedly, related to cell death, although abundant evidence points at oscillating oxygen levels, instead of permanent low pO2, as the most detrimental factor. Different cell types can consume oxygen at different rates and, most interestingly, some cells can shift from low to high consumption according to the metabolic demand. Hence, we can assume that, in the intracellular compartment, oxygen tension varies from low to high levels depending on both supply and consumption. Critical Issues: The positive balance between supply and consumption leads to a pro-oxidative environment, with some cell types facing hypoxia/hyperoxia cycles, whereas some others are under fairly constant oxygen tension. Future Directions: Within this frame, the alterations of oxygen levels (dysoxia) are critical in two paradigmatic organs, the heart and brain, under physiological and pathological conditions and the interactions of oxygen with other physiologically relevant gases, such as nitric oxide, can alternatively contribute to the worsening or protection of ischemic organs. Further, the effects of dysoxia are of pivotal importance for iron metabolism. Antioxid. Redox Signal. 37, 972-989.

Corrigendum: Inside the Alterations of Circulating Metabolome in Antarctica: The Adaptation to Chronic Hypoxia.

[This corrects the article DOI: 10.3389/fphys.2022.819345.].

Inside the Alterations of Circulating Metabolome in Antarctica: The Adaptation to Chronic Hypoxia.

Although the human body may dynamically adapt to mild and brief oxygen shortages, there is a growing interest in understanding how the metabolic pathways are modified during sustained exposure to chronic hypoxia. Located at an equivalent altitude of approximately 3,800 m asl, the Concordia Station in Antarctica represents an opportunity to study the course of human adaption to mild hypoxia with reduced impact of potentially disturbing variables else than oxygen deprivation. We recruited seven healthy subjects who spent 10 months in the Concordia Station, and collected plasma samples at sea level before departure, and 90 days, 6 months, and 10 months during hypoxia. Samples were analyzed by untargeted liquid chromatography high resolution mass spectrometry to unravel how the non-polar and polar metabolomes are affected. Statistical analyses were performed by clustering the subjects into four groups according to the duration of hypoxia exposure. The non-polar metabolome revealed a modest decrease in the concentration of all the major lipid classes. By contrast, the polar metabolome showed marked alterations in several metabolic pathways, especially those related to amino acids metabolism, with a particular concern of arginine, glutamine, phenylalanine, tryptophan, and tyrosine. Remarkably, all the changes were evident since the first time point and remained unaffected by hypoxia duration (with the exception of a slight return of the non-polar metabolome after 6 months), highlighting a relative inability of the body to compensate them. Finally, we identified a few metabolic pathways that emerged as the main targets of chronic hypoxia.

Mitochondrial dysfunctions in neurodegenerative diseases: role in disease pathogenesis, strategies for analysis and therapeutic prospects.

Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes, the mitochondria are required for multiple pivotal processes that include the production of biological energy, the biosynthesis of reactive oxygen species, the control of calcium homeostasis, and the triggering of cell death. The disruption of anyone of these processes has been shown to impact strongly the function of all cells, but especially of neurons. In this review, we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis, Parkinson's disease and Alzheimer's disease. We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria's life cycle: fusion, fission, production of reactive oxygen species and energy failure. Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes. Therefore, in order to get in depth insights into their health status in neurodegenerative diseases, we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes. Current techniques include Mitostress, Mitotracker, transmission electron microscopy, oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health. We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction. These include canonical drugs, natural compounds, supplements, lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy. In conclusion, because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases, it is critical to develop novel methods to measure the mitochondrial state, and novel therapeutic strategies aimed at improving their health.

Can Erythropoietin Reduce Hypoxemic Neurological Damages in Neonates With Congenital Heart Defects?

Congenital heart defects (CHD), the most common cause of birth defects with increasing birth prevalence, affect nearly 1% of live births worldwide. Cyanotic CHD are characterized by hypoxemia, with subsequent reduced oxygen delivery to the brain, especially critical during brain development, beginning in the fetus and continuing through the neonatal period. Therefore, neonates with CHD carry a high risk for neurological comorbidities, even more frequently when there are associated underlying genetic disorders. We review the currently available knowledge on potential prevention strategies to reduce brain damage induced by hypoxemia during fetal development and immediately after birth, and the role of erythropoietin (EPO) as a potential adjunctive treatment. Maternal hyper-oxygenation had been studied as a potential therapeutic to improve fetal oxygenation. Despite demonstrating some effectiveness, maternal hyper-oxygenation has proven to be impractical for extensive clinical application, thus prompting the investigation of specific pathways for pharmacological intervention. Among those, the role of antioxidant pathways and Hypoxia Inducible Factors (HIF) have been studied for their involvement in the protective response to hypoxic injury. One of the proteins induced by HIF, EPO, has properties of being anti-apoptotic, antioxidant, and protective for neurons, astrocytes, and oligodendrocytes. In human trials, EPO administration in neonates with hypoxic ischemic encephalopathy (HIE) significantly reduced the neurological hypoxemic damages in several reported studies. Currently, it is unknown if the mechanisms of pathophysiology of cyanotic CHD are like HIE. Neonates with cyanotic CHD are exposed to both chronic hypoxemia and episodes of acute ischemia-reperfusion injury when undergo cardiopulmonary bypass surgery requiring aortic cross-clamp and general anesthesia. Our review supports future trials to evaluate the potential efficiency of EPO in reducing the hypoxemic neurologic damages in neonates with CHD. Furthermore, it suggests the need to identify early biomarkers of hypoxia-induced neurological damage, which must be sensitive to the neuroprotective effects of EPO.

Link between serum lipid signature and prognostic factors in COVID-19 patients.

Although the serum lipidome is markedly affected by COVID-19, two unresolved issues remain: how the severity of the disease affects the level and the composition of serum lipids and whether serum lipidome analysis may identify specific lipids impairment linked to the patients' outcome. Sera from 49 COVID-19 patients were analyzed by untargeted lipidomics. Patients were clustered according to: inflammation (C-reactive protein), hypoxia (Horowitz Index), coagulation state (D-dimer), kidney function (creatinine) and age. COVID-19 patients exhibited remarkable and distinctive dyslipidemia for each prognostic factor associated with reduced defense against oxidative stress. When patients were clustered by outcome (7 days), a peculiar lipidome signature was detected with an overall increase of 29 lipid species, including-among others-four ceramide and three sulfatide species, univocally related to this analysis. Considering the lipids that were affected by all the prognostic factors, we found one sphingomyelin related to inflammation and viral infection of the respiratory tract and two sphingomyelins, that are independently related to patients' age, and they appear as candidate biomarkers to monitor disease progression and severity. Although preliminary and needing validation, this report pioneers the translation of lipidome signatures to link the effects of five critical clinical prognostic factors with the patients' outcomes.

Differential Redox State and Iron Regulation in Chronic Obstructive Pulmonary Disease, Acute Respiratory Distress Syndrome and Coronavirus Disease 2019.

In patients affected by Acute Respiratory Distress Syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD) and Coronavirus Disease 2019 (COVID-19), unclear mechanisms negatively interfere with the hematopoietic response to hypoxia. Although stimulated by physiological hypoxia, pulmonary hypoxic patients usually develop anemia, which may ultimately complicate the outcome. To characterize this non-adaptive response, we dissected the interplay among the redox state, iron regulation, and inflammation in patients challenged by either acute (ARDS and COVID-19) or chronic (COPD) hypoxia. To this purpose, we evaluated a panel of redox state biomarkers that may integrate the routine iron metabolism assays to monitor the patients' inflammatory and oxidative state. We measured redox and hematopoietic regulators in 20 ARDS patients, 20 ambulatory COPD patients, 9 COVID-19 ARDS-like patients, and 10 age-matched non-hypoxic healthy volunteers (controls). All the examined pathological conditions induced hypoxia, with ARDS and COVID-19 depressing the hematopoietic response without remarkable effects on erythropoietin. Free iron was higher than the controls in all patients, with higher levels of hepcidin and soluble transferrin receptor in ARDS and COVID-19. All markers of the redox state and antioxidant barrier were overexpressed in ARDS and COVID-19. However, glutathionyl hemoglobin, a candidate marker for the redox imbalance, was especially low in ARDS, despite depressed levels of glutathione being present in all patients. Although iron regulation was dysfunctional in all groups, the depressed antioxidant barrier in ARDS, and to a lesser extent in COVID-19, might induce greater inflammatory responses with consequent anemia.

Mitochondrial Metabolism as Target of the Neuroprotective Role of Erythropoietin in Parkinson's Disease.

Existing therapies for Parkinson's disease (PD) are only symptomatic. As erythropoietin (EPO) is emerging for its benefits in neurodegenerative diseases, here, we test the protective effect driven by EPO in in vitro (SH-SY5Y cells challenged by MPP+) and in vivo (C57BL/6J mice administered with MPTP) PD models. EPO restores cell viability in both protective and restorative layouts, enhancing the dopaminergic recovery. Specifically, EPO rescues the PD-induced damage to mitochondria, as shown by transmission electron microscopy, Mitotracker assay and PINK1 expression. Moreover, EPO promotes a rescue of mitochondrial respiration while markedly enhancing the glycolytic rate, as shown by the augmented extracellular acidification rate, contributing to elevated ATP levels in MPP+-challenged cells. In PD mice, EPO intrastriatal infusion markedly improves the outcome of behavioral tests. This is associated with the rescue of dopaminergic markers and decreased neuroinflammation. This study demonstrates cellular and functional recovery following EPO treatment, likely mediated by the 37 Kda isoform of the EPO-receptor. We report for the first time, that EPO-neuroprotection is exerted through restoring ATP levels by accelerating the glycolytic rate. In conclusion, the redox imbalance and neuroinflammation associated with PD may be successfully treated by EPO.

Iron and Sphingolipids as Common Players of (Mal)Adaptation to Hypoxia in Pulmonary Diseases.

Hypoxia, or lack of oxygen, can occur in both physiological (high altitude) and pathological conditions (respiratory diseases). In this narrative review, we introduce high altitude pulmonary edema (HAPE), acute respiratory distress syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), and Cystic Fibrosis (CF) as examples of maladaptation to hypoxia, and highlight some of the potential mechanisms influencing the prognosis of the affected patients. Among the specific pathways modulated in response to hypoxia, iron metabolism has been widely explored in recent years. Recent evidence emphasizes hepcidin as highly involved in the compensatory response to hypoxia in healthy subjects. A less investigated field in the adaptation to hypoxia is the sphingolipid (SPL) metabolism, especially through Ceramide and sphingosine 1 phosphate. Both individually and in concert, iron and SPL are active players of the (mal)adaptation to physiological hypoxia, which can result in the pathological HAPE. Our aim is to identify some pathways and/or markers involved in the physiological adaptation to low atmospheric pressures (high altitudes) that could be involved in pathological adaptation to hypoxia as it occurs in pulmonary inflammatory diseases. Hepcidin, Cer, S1P, and their interplay in hypoxia are raising growing interest both as prognostic factors and therapeutical targets.

Hyperoxia and oxidative stress in anesthesia and critical care medicine.

Oxygen administration is particularly relevant in patients undergoing surgery under general anesthesia and in those who suffer from acute or critical illness. Nevertheless, excess O2, or hyperoxia, is also known to be harmful. Toxicity arises from the enhanced formation of reactive oxygen species (ROS) that, exceeding the antioxidant defense, may generate oxidative stress. Oxidative stress markers are used to quantify ROS toxicity in clinical and non-clinical settings and represent a promising tool to assess the optimal FiO2 in anesthesia and critical care setting. Despite controversial, the guidelines for the regulation of FiO2 in such settings suggest the adoption of high perioperative oxygen levels. However, hyperoxia has also been shown to be an independent mortality risk factor in critically ill patients. In this literature review, we discuss the biochemical mechanisms behind oxidative stress and the available biomarkers for assessing the pro-oxidant vs antioxidant status. Then, we summarize recent knowledge on the hyperoxia-related consequences in the most common anesthesia and critical care settings, such as traumatic brain injury or cardiac arrest. To this purpose, we searched the PubMed database according to the following combination of key words: ("hyperoxia" OR "FiO2" OR "oxygen therapy") AND ("oxidative stress" OR "ROS" OR "RNS" OR "lipid peroxidation") AND ("anesthesia" OR "surgery" OR "intensive care"). We focused in the results from the past 20 years. Available evidence points toward a conservative monitoring and use of oxygen, unless there is solid proof of its efficacy.

Oxidative Stress Markers to Investigate the Effects of Hyperoxia in Anesthesia.

Oxygen (O2) is commonly used in clinical practice to prevent or treat hypoxia, but if used in excess (hyperoxia), it may act as toxic. O2 toxicity arises from the enhanced formation of Reactive Oxygen Species (ROS) that exceed the antioxidant defenses and generate oxidative stress. In this study, we aimed at assessing whether an elevated fraction of inspired oxygen (FiO2) during and after general anesthesia may contribute to the unbalancing of the pro-oxidant/antioxidant equilibrium. We measured five oxidative stress biomarkers in blood samples from patients undergoing elective abdominal surgery, randomly assigned to FiO2 = 0.40 vs. 0.80: hydroperoxides, antioxidants, nitrates and nitrites (NOx), malondialdehyde (MDA), and glutathionyl hemoglobin (HbSSG). The MDA concentration was significantly higher 24 h after surgery, and the body antioxidant defense lower, in the FiO2 = 0.80 group with respect to both the FiO2 = 0.40 group and the baseline values (p ≤ 0.05, Student's t-test). HbSSG in red blood cells was also higher in the FiO2 = 0.80 group at the end of the surgery. NOx was higher in the FiO2 = 0.80 group than the FiO2 = 0.40 group at t = 2 h after surgery. MDA, the main end product of the peroxidation of polyunsaturated fatty acids directly influenced by FiO2, may represent the best marker to assess the pro-oxidant/antioxidant equilibrium after surgery.