No description available.

PURPOSE: To investigate the plausibility of clinically significant oxygen toxicity in patients with retinal disorders being treated with hyperoxia therapy. Supplemental oxygen therapy is a promising form of treatment that may help reduce ischemia and the subsequent symptoms in patients suffering from diabetic retinopathy (DR), retinal vein occlusions (RVOs), and age-related macular degeneration (AMD). Currently, few studies perform ongoing assessments of current hyperoxia trials in patient populations. By investigating a current cohort of patients using supplemental oxygen to mitigate symptoms in their ocular conditions, we hope to demonstrate the extremely low likelihood of oxygen toxicity in patients utilizing hyperoxia therapy. Through these results, we hope to demonstrate that supplemental oxygen therapy is a viable, safe method of treatment for patients with ocular disorders. METHODS: A cohort of 16 patients was analyzed for changes in their C Reactive Protein (CRP), white blood cell count (WBC), hematocrit (Hct), and hemoglobin (Hb) levels after continuous use of hyperoxia therapy as part of treatment for varying retinal disorders. All study patients were diagnosed and under treatment at Beth Israel Deaconess Medical Center in Boston, MA. Patients diagnosed with diabetic retinopathy, retinal vein occlusions, or age-related macular degeneration were included in the study. Each of these patients must have also been prescribed 5 L/min of nocturnal hyperoxia therapy. Patients with insufficient data either before or after beginning the hyperoxia therapy were excluded. Primary outcome variables were arranged as pre- and post- hyperoxia therapy data points for CRP, WBC, Hb, and Hct. P-values below 0.05 would indicate statistically significant risk of oxygen toxicity in these variables under the current hyperoxia treatment. RESULTS: The mean age of the sample population was 64, with 6 of the 16 patients diagnosed with diabetes (37.5%). Patient groups were divided into diabetic vs. non-diabetic to assess whether or not one group was affected differently by the hyperoxia therapy. Results showed p-values well over 0.05 for both groups, indicating that oxygen toxicity is not a major risk factor when using supplemental oxygen under the study’s conditions. CONCLUSION: A large number of patients with diabetes suffer from retinal problems, especially with the onset of old age. These problems eventually require treatment via eye injections, laser, and even surgery in order to preserve vision and mitigate edema and ischemia. Given the high cost and invasive nature of these procedures, hyperoxia therapy provides a safe and potentially beneficial alternative to mitigate the symptoms of these disorders. This study hoped to demonstrate the plausibility of widespread clinical application for supplemental oxygen therapy in retina patients, while concluding that oxygen toxicity is not a significant risk factor in this type of treatment. The outcomes of this study support this hypothesis, and lay the groundwork for future studies that may assess the risks of oxygen toxicity on a larger scale. More research is required to gauge the true risks of oxygen toxicity in patients using supplemental oxygen. A case-controlled longitudinal study would also prove useful in providing data on changes in visual acuity and other experimental factors of interest, while accounting for several limitations present in this study. / 2021-06-17T00:00:00Z

No description available.

Chapter 1 introduces the phenomenon of oxygen toxicity and the central role played by oxygen free radicals, most notably the superoxide radical anion. The technique of spin trapping, whereby reactive free radicals are studied and identified, is then introduced. The synthesis of improved spin traps for superoxide by the preparation of 1-pyrroline 1-oxides bearing a C-3 ester or alkyl halide substituent is then discussed. Chapter 2 describes the preparation of 2-(prop-2-enyl)-aldehydes, 2-dimethoxymethylaldehydes and a 2-phenylthiomethylaldehyde. Bromination of 5,5-dimethyl-1-(prop-2-enyl)-1-pyrroline 1-oxide did not give rise to addition at the C=C double bond but recovery of the nitrone and a hydroxamic acid. Similarly, hydrohalogenation of the alkenyl-nitrone did not lead to addition at the C=C double bond. The preparation and utility of 3-(ethoxycarbonylprop-2-enyl)-5,5-dimethyl-1-pyrroline 1-oxide is then described. Chapter 3 details the preparation of 3-dimethoxymethyl-1-pyrroline 1-oxides. Acid-catalysed deprotection of these nitrone acetals did not result in the formation of the expected 3-aldehydo-5,5-dimethyl-1-pyrroline 1-oxides. Chapter 4 deals with the preparation of 5,5-dimethyl-3-phenylthiomethyl-1-pyrroline 1-oxide. Conversion of the phenylthiomethyl group to an iodomethyl group led to the loss of the nitrone. Chlorination of the nitrone gave 4-methyl-4-nitro-2-phenylthiomethylpentanoic acid. Oxidation of 5,5-dimethyl-3-ethoxycarbonyl-1-hydroxypyrrolidine resulted in the dimeric nitrone 3,3'-bis(ethoxycarbonyl)-5,5,5',5'-tetramethyl-3,3'-bi-1-pyrrolinyl 1,1-dioxide being isolated. Chapter 5 concerns the synthetic utility of α-bromoaldehydes. The preparation of 5,5-dimethyl-3-benzenesulphonyl-1-pyrroline 1-oxide is then described. Alkylation of the nitrone in the presence of sodium hydride with methylbromoacetate gave the C-3 disubstituted nitrone, 3-benzenesulphonyl-5,5-dimethyl-3-methoxycarbonylmethyl-1-pyrroline 1-oxide. Chapter 6 concerns the spin trapping reactions of the nitrones prepared in this thesis. The ESR spectra of the hydrogen atom adducts showed the magnetic non-equivalence of the β-hydrogens owing to the presence of the C-3 substituent. Spin trapping of the <I>t</I>-butoxy radical was found to be stereospecific. Apparent selectivity for the hydroxyl radical was found as no spin adducts were detected with the superoxide radical anion.

Bronchopulmonary dysplasia (BPD) is a chronic neonatal lung injury (CNLI) affecting infants of < 32 weeks gestation, which has a significant associated morbidity and mortality. The hallmarks of BPD as seen in the current era are arrested alveologenesis and parenchymal thickening. Those most severely affected may develop pulmonary hypertension which worsens the prognosis. No effective preventive therapy exists. Generation of damaging reactive oxygen species is implicated in its development. The more recently recognized reactive nitrogen species may also contribute to this disease. Thus, there is considerable interest in preventive antioxidant therapies, but results to date have not been promising. Newborn rats, exposed to 60% O2 for 14 days, develop a parenchymal injury and pulmonary hypertension that resembles the morphological features of human BPD. Previous studies have shown that following exposure to 60% O2, a pulmonary influx of neutrophils is followed by that of macrophages. Inhibiting the influx of neutrophils prevents the generation of reactive oxygen species, while simultaneously enhancing postnatal lung growth. Other interventions have shown that development of pulmonary hypertension is dependent upon increases in both 8-isoprostane and its downstream regulator of vascular tone, endothelin-1. Gentler ventilation strategies, incorporated to minimize induction of stretch-mediated pro-inflammatory cytokines, have shown benefits of permissive hypercapnia in adult lung injury. Multicentre clinical trials of permissive hypercapnia in neonates have not shown benefit. Therapeutic hypercapnia has been demonstrated to have a protective effect of PaCO2 in both acute studies of ventilator-induced and ischemia-reperfusion injuries in animal models. In the studies reported herein, therapeutic hypercapnia was found to completely protect against CNLI and attenuate 60% O2-induced macrophage-derived protein nitration. The likely nitrating agent was macrophage-derived peroxynitrite. The critical role of peroxynitrite, in the development of chronic neonatal lung injury in this model, was confirmed using a peroxynitrite decomposition catalyst. This protected against the impairments of alveolarization and of pulmonary vascularization induced by 60% O2. These results suggest a more significant role for reactive nitrogen species than previously recognized. Finally, preliminary evidence is presented supporting a role for neutrophil-derived elastase in initiating the macrophage influx in the lungs, required for peroxynitrite generation, during 60% O2-mediated injury.

Bronchopulmonary dysplasia (BPD) is a chronic neonatal lung injury (CNLI) affecting infants of < 32 weeks gestation, which has a significant associated morbidity and mortality. The hallmarks of BPD as seen in the current era are arrested alveologenesis and parenchymal thickening. Those most severely affected may develop pulmonary hypertension which worsens the prognosis. No effective preventive therapy exists. Generation of damaging reactive oxygen species is implicated in its development. The more recently recognized reactive nitrogen species may also contribute to this disease. Thus, there is considerable interest in preventive antioxidant therapies, but results to date have not been promising. Newborn rats, exposed to 60% O2 for 14 days, develop a parenchymal injury and pulmonary hypertension that resembles the morphological features of human BPD. Previous studies have shown that following exposure to 60% O2, a pulmonary influx of neutrophils is followed by that of macrophages. Inhibiting the influx of neutrophils prevents the generation of reactive oxygen species, while simultaneously enhancing postnatal lung growth. Other interventions have shown that development of pulmonary hypertension is dependent upon increases in both 8-isoprostane and its downstream regulator of vascular tone, endothelin-1. Gentler ventilation strategies, incorporated to minimize induction of stretch-mediated pro-inflammatory cytokines, have shown benefits of permissive hypercapnia in adult lung injury. Multicentre clinical trials of permissive hypercapnia in neonates have not shown benefit. Therapeutic hypercapnia has been demonstrated to have a protective effect of PaCO2 in both acute studies of ventilator-induced and ischemia-reperfusion injuries in animal models. In the studies reported herein, therapeutic hypercapnia was found to completely protect against CNLI and attenuate 60% O2-induced macrophage-derived protein nitration. The likely nitrating agent was macrophage-derived peroxynitrite. The critical role of peroxynitrite, in the development of chronic neonatal lung injury in this model, was confirmed using a peroxynitrite decomposition catalyst. This protected against the impairments of alveolarization and of pulmonary vascularization induced by 60% O2. These results suggest a more significant role for reactive nitrogen species than previously recognized. Finally, preliminary evidence is presented supporting a role for neutrophil-derived elastase in initiating the macrophage influx in the lungs, required for peroxynitrite generation, during 60% O2-mediated injury.

Oxygen supplementation has been an important part of respiratory failure treatment in all fields of clinical medicine, especially on intensive care units (hereinafter referred to as ICU). Oxygen therapy is a life-saving measure but indiscriminate administration of oxygen can cause lung and nerve damage and consequently increase morbidity and mortality (1). In clinical practice we often encounter mechanically ventilated patients with high partial pressures of oxygen in arterial blood (5) which should direct our attention to possible consequences and have reliable data how is oxygen treatment managed. This thesis focuses on the exposure to toxic concentrations of oxygen on the resuscitation ward. The aim of this thesis is to determine whether patients are exposed to high concentrations of oxygen. Two other aims of this study are to find out how long are patients in a state of hyperoxemia and whether medical staff reacts to measured partial pressures of oxygen (hereinafter referred to as paO2) values in these patients by reducing oxygen fraction (hereinafter referred to as FiO2) on the ventilator. The research part of this thesis is a quantitative observational retrospective research. The inclusion criteria were hospital admission from 1st July to 1st October 2019, at least two paO2 values greater...

A redução univalente de oxigênio molecular nas células produz intermediários altamente reativos tais como o íon radical Superóxido (O-&#8226;2), o radical hidroxil (HO&#8226;) e o peróxido de hidrogênio (H2O2). Níveis muito altos ou baixos de tais espécies representam séria ameaça ao metabolismo celular. Diferentes estados patológicos têm sido relacionados com níveis anormais destas espécies em eritrócitos e plaquetas. A proteção biológica contra efeitos tóxicos associados com níveis excessivos de espécies ativadas de oxigênio, tem sido atribuída a três enzimas principais presentes em eritrócitos e outras células: superóxido dismutase, catalase e glutationa peroxidase. Neste trabalho, foram feitas dosagens dessas enzimas protetoras em eritrócitos de indivíduos portadores de porfiria aguda intermitente. Esta doença caracteriza-se por um defeito na biossíntese de heme e clinicamente manifesta-se por dor abdominal intensa, paralisia e distúrbios neuropsíquicos. Foram encontrados nos pacientes em crise aguda atividades elevadas de superóxido dismutase e de glutationa peroxidase enquanto que a atividade de catalase permaneceu normal. Tais resultados apontam a possibilidade de que as manifestações clínicas de IAP relacionadas com toxicidade por oxigênio. Estejam Comparou-se também a atividade destas três enzimas em eritrócitos de residentes na cidade de são Paulo com o de moradores de Vila Parisi, conhecida pelo seu altíssimo nível de poluiçao atmosférica. Os níveis de superóxido dismutase e de glutationa peroxidase são bem mais elevados (cerca de 1,5 vezes) nos indivíduos residentes em Vila Parisi. A elevação da concentração intracelular destas enzimas pode ser sua resposta ao aumento da taxa de oxidação da oxihemoglobina, a qual é conhecida fonte de íons superóxido. Estes dados demonstram profundas diferenças no metabolismo de 02 entre esses dois grupos e talvez uma possível adaptação metabólica dos moradores de Vila Parisi aos altos níveis de poluição a que estão expostos. / The univalent reduction of molecular oxygen in cells produces very reactive species such as the superoxide anion (O-&#8226;2), the hydroxyl radical (HO&#8226;) and hydrogen peroxide (H2O2). Abnormally high or low concentrations of such species may represent a serious threat to the cellular metabolism. Indeed, several disorders have been associated with abnormal levels of these species in erythrocytes and platelets.The biological protection against toxic effects due to excessive levels of activated species of molecular oxygen has been attributed mainly to three enzymes occurring in erythrocytes and other cells: superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase. In the present work, we report the activities of SOD, GSH-Px and catalase in the erythrocytes of patients with intermittent acute porphyria (IAP), an inborn error in the heme biosynthetic pathway. The clinical manifestations of IAP include abdominal pain and neuropsychiatric symptons. In patients undergoing acute attack, we found increased levels of SOD and GSH-Px, while that of catalase remains unchanged. These results point to the possibility that the clinical manifestations of IAP are related to oxygen toxicity. We have also compared the activities of these enzymes in residents of the city of são Paulo (Brazil) and in subjects living in Vila Parisi (Cubatão, SP, Brazil), a village submitted to high levels of atmospheric pollution. The erythrocyte SOD and GSH-Px levels were found to be ca. 1.5 fold higher in residents of Vila Parisi. These high intracellular enzyme concentrations may reflect a biological defense against an increase in the rate of oxyhemoglobin oxidation, known to be a source of superoxide species. Our results point to important differences between the two populations with respect to the metabolism of oxygen and, perhaps, a metabolic adaptation in the residents of Vila Parisi to the dramatically high levels of atmospheric pollution.

A redução univalente de oxigênio molecular nas células produz intermediários altamente reativos tais como o íon radical Superóxido (O-&#8226;2), o radical hidroxil (HO&#8226;) e o peróxido de hidrogênio (H2O2). Níveis muito altos ou baixos de tais espécies representam séria ameaça ao metabolismo celular. Diferentes estados patológicos têm sido relacionados com níveis anormais destas espécies em eritrócitos e plaquetas. A proteção biológica contra efeitos tóxicos associados com níveis excessivos de espécies ativadas de oxigênio, tem sido atribuída a três enzimas principais presentes em eritrócitos e outras células: superóxido dismutase, catalase e glutationa peroxidase. Neste trabalho, foram feitas dosagens dessas enzimas protetoras em eritrócitos de indivíduos portadores de porfiria aguda intermitente. Esta doença caracteriza-se por um defeito na biossíntese de heme e clinicamente manifesta-se por dor abdominal intensa, paralisia e distúrbios neuropsíquicos. Foram encontrados nos pacientes em crise aguda atividades elevadas de superóxido dismutase e de glutationa peroxidase enquanto que a atividade de catalase permaneceu normal. Tais resultados apontam a possibilidade de que as manifestações clínicas de IAP relacionadas com toxicidade por oxigênio. Estejam Comparou-se também a atividade destas três enzimas em eritrócitos de residentes na cidade de são Paulo com o de moradores de Vila Parisi, conhecida pelo seu altíssimo nível de poluiçao atmosférica. Os níveis de superóxido dismutase e de glutationa peroxidase são bem mais elevados (cerca de 1,5 vezes) nos indivíduos residentes em Vila Parisi. A elevação da concentração intracelular destas enzimas pode ser sua resposta ao aumento da taxa de oxidação da oxihemoglobina, a qual é conhecida fonte de íons superóxido. Estes dados demonstram profundas diferenças no metabolismo de 02 entre esses dois grupos e talvez uma possível adaptação metabólica dos moradores de Vila Parisi aos altos níveis de poluição a que estão expostos. / The univalent reduction of molecular oxygen in cells produces very reactive species such as the superoxide anion (O-&#8226;2), the hydroxyl radical (HO&#8226;) and hydrogen peroxide (H2O2). Abnormally high or low concentrations of such species may represent a serious threat to the cellular metabolism. Indeed, several disorders have been associated with abnormal levels of these species in erythrocytes and platelets.The biological protection against toxic effects due to excessive levels of activated species of molecular oxygen has been attributed mainly to three enzymes occurring in erythrocytes and other cells: superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase. In the present work, we report the activities of SOD, GSH-Px and catalase in the erythrocytes of patients with intermittent acute porphyria (IAP), an inborn error in the heme biosynthetic pathway. The clinical manifestations of IAP include abdominal pain and neuropsychiatric symptons. In patients undergoing acute attack, we found increased levels of SOD and GSH-Px, while that of catalase remains unchanged. These results point to the possibility that the clinical manifestations of IAP are related to oxygen toxicity. We have also compared the activities of these enzymes in residents of the city of são Paulo (Brazil) and in subjects living in Vila Parisi (Cubatão, SP, Brazil), a village submitted to high levels of atmospheric pollution. The erythrocyte SOD and GSH-Px levels were found to be ca. 1.5 fold higher in residents of Vila Parisi. These high intracellular enzyme concentrations may reflect a biological defense against an increase in the rate of oxyhemoglobin oxidation, known to be a source of superoxide species. Our results point to important differences between the two populations with respect to the metabolism of oxygen and, perhaps, a metabolic adaptation in the residents of Vila Parisi to the dramatically high levels of atmospheric pollution.

Die rasanten Fortschritte in der neonatalen Intensivmedizin haben zwar die Ueberlebenschancen von Fruehgeborenen enorm verbessert, aber auch viele Probleme und Fragen aufgeworfen. In dieser Arbeit wurde untersucht, ob Hyperoxie Einfluss nimmt auf die Expression von apoptotischen Genen, Wachstumsfaktoren und Zytokinen und so ueber verschiedene Mechanismen und Signalwege zu einem Ungleichgewicht der ueber das neuronale Ueberleben entscheidenden Faktoren fuehrt. 6-Tage alte Ratten wurden fuer bestimme Zeitabschnitte (2, 6, 12, 24, 48, 72 Stunden) einer 80%igen Sauerstoffkonzentration ausgesetzt. In dieser Arbeit konnte am unreifen Rattengehirn nachgewiesen werden, dass eine 80%ige Sauerstoffkonzentration in der Atemluft maximal nach 12 bis 24 Stunden zu einer ausgepraegten, diffusen apoptotischen Neurodegeneration im Gehirn fuehrt. Die Exposition mit hoher Sauerstoffkonzentration fuehrte im unreifen Gehirn zu einer deutlich verminderten Expression der Neurotrophinen, wie deren Signalproteine ERK 1/2 und Akt. Als spezifischer Nachweis fuer eine apoptotische Neurodegeneration wurden neben dem histologischen Verfahren auf molekularer Ebene apoptotische Gene untersucht. Unter Hyperoxie kam es zu einer erhoehten Expression des Todesrezeptors Fas und einer gesteigerten Aktivitaet von Caspase-3.Des Weiteren fand sich infolge der Hyperoxieexposition ein drastischer Anstieg der inflammatorischen Zytokine IL-1beta und IL-18. Es zeigt sich also, dass hohe Sauerstoffkonzentrationen in einer sehr vulnerablen Phase der Hirnentwicklung (Phase des rapiden Hirnwachstums) zu massiven Veraenderungen fuehren, welche den bisher ungeklaerten diffusen Neuronenuntergang bei Fruehgeborenen erklaeren koennten. Die vorliegenden Ergebnisse implizieren aeu§erste Vorsicht bei der therapeutischen Anwendung von Sauerstoff bei Fruehgeborenen, fuer die die postnatalen Konditionen, verglichen mit den intrauterinen Bedingungen, immer hyperoxisch sind und die noch ueber ein unreifes Antioxidationssystem verfuegen. / Infants born prematurely may develop neurocognitive deficits without an obvious cause. Oxygen, which is widely used in neonatal medicine, constitutes one possible contributing neurotoxic factor, because it can trigger neuronal apoptosis in the developing brain of rodents. Premature infants are exposed to partial oxygen pressures that are fourfold higher compared to intrauterine conditions, even if no supplemental oxygen is administered. Here is reported that short exposures to nonphysiologic oxygen levels can trigger apoptotic neurodegeneration in the developing brain. Vulnerability to oxygen neurotoxicity is confined to the first 2 weeks of life, a period characterized by rapid growth, which in humans expands from the sixth month of pregnancy to the third year of life. Hyperoxia caused decreased expression of neurotrophins, and inactivation of survival signalling proteins extracellular signal-regulated kinase (ERK1/2), and protein kinase B (Akt). In addition we hypothesized that two caspase-1-processed cytokines, interleukin (IL)-1beta and IL-18, are involved in oxygen-induced neuronal cell death. Six-day-old Wistar rats were exposed to 80% oxygen for various time periods (2, 6, 12, 24, 48, 72 hours). Neuronal cell death in the brain, as assessed by silver staining, peaked at 12 to 24 hours and was preceded by a marked increase in mRNA of IL-1beta, IL-18 and FAS and a decrease in mRNA and protein levels of neurotrophins and ERK1/2 and Akt Our findings reveal mechanisms that could potentially damage the developing brain of human premature neonates.