Treatment of central retinal vein occlusion.
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Adult↗
Biomedical subjects
G C Brown
Publications and source records attributed to G C Brown.
Nitric oxide inhibition of cytochrome oxidase and mitochondrial respiration: implications for inflammatory, neurodegenerative and ischaemic pathologies.
Nitric oxide (NO) at high levels is cytotoxic, and may be involved in a range of inflammatory, neurodegenerative, and cardiovascular/ischaemic pathologies. The mechanism of NO-induced cytotoxicity is unclear. Recently we and others have found that low (nanomolar) levels of NO reversibly inhibit mitochondrial respiration by binding to the oxygen binding site of cytochrome oxidase in competition with oxygen. This raises the apparent K(m) for oxygen of mitochondrial respiration into the physiological range, potentially making respiration sensitive to the oxygen level. The NO inhibition of oxygen consumption was seen in isolated cytochrome oxidase, mitochondria, brain nerve terminals, and cultured cells. Cultured astrocytes activated to express the inducible from of NO synthase produced up to 1 microM NO and strongly inhibited their own cellular respiration rate. This respiratory inhibition was rapidly reversed by removing the NO, and was due to the inhibition of cytochrome oxidase. These results suggest that any cell producing high levels of NO will inhibit its own respiration and that of surrounding cells, and make the respiration rate sensitive to the oxygen level. This inhibition of energy metabolism may contribute to cytotoxicity or cytostasis in some pathologies.
Animals↗
Ca2+ stimulates both the respiratory and phosphorylation subsystems in rat heart mitochondria.
Stimulation of mitochondrial respiration by physiological concentrations of Ca2+ was studied to determine which components of oxidative phosphorylation are affected by Ca2+. The kinetic dependence of the respiratory chain, phosphorylation subsystem and proton leak on the mitochondrial membrane potential in isolated rat heart mitochondria respiring on 2-oxoglutarate or succinate was measured at two different concentrations of external free Ca2+. The results show that proton leak is not directly affected by Ca2+, but that both the respiratory and phosphorylation systems can be directly stimulated by Ca2+ depending on conditions. Although Ca2+ directly stimulates the phosphorylation system, this has relatively little effect on respiration rate with 2-oxoglutarate in States 3 and 4 because the subsystem has little control over respiration. However, in intermediate states, the phosphorylation system has greater control and Ca2+ stimulation of this system contributes substantially to the stimulation of respiration and phosphorylation. In the case of succinate oxidation neither the respiratory subsystem nor the phosphorylation system is stimulated by Ca2+.
Animals↗
Molecular control analysis: control within proteins and molecular processes.
Molecular control analysis is a method for analysing the extent to which the different elementary steps or rate constants within a molecular process limit the steady-state rate (or other variables) of that process. Any process which may be described by a kinetic diagram of transitions between states of the system may be analysed by molecular control analysis, and this approach has previously been used to analyse control within enzymes, transporters, enzyme complexes, channelled pathways, and group-transfer pathways. We outline the theory of molecular control analysis here, and illustrate its use by analysing control within enzymes (three beta-lactamases). Further potential applications include signal-transduction processes, protein folding, and chemical reactions.
Animals↗
Rapid reduction of nitric oxide by mitochondria, and reversible inhibition of mitochondrial respiration by nitric oxide.
Nitric oxide (NO) inhibited the respiration rate of mitochondria isolated from rat heart at sub-micromolar concentrations of NO. The inhibition was rapidly and completely reversible, indicating that NO does not damage mitochondria. The sensitivity of respiration to NO depended on the oxygen concentration, substrate type and respiratory state of the mitochondria, consistent with NO competing with oxygen at cytochrome oxidase. Mitochondria catalysed a rapid rate of NO breakdown, which was greater in the absence of oxygen and was partly inhibited by cyanide and azide, suggesting that at least part of the NO breakdown was due to reduction of NO by cytochrome oxidase. The rapid rate of this breakdown suggests that mitochondrial breakdown of NO may be significant physiologically.
Animals↗
Paradoxical control properties of enzymes within pathways: can activation cause an enzyme to have increased control?
It is widely assumed that within a metabolic pathway inhibition of an enzyme causes the control exerted by that enzyme over the flux through its own reaction to increase, whereas activation causes its control to decrease. This assumption forms the basis of a number of experimental methods. For a pathway conceptually divided into two enzyme groups connected via a single metabolite we have derived a general condition under which this assumption is false, and thus the pathway shows paradoxical control behaviour, i.e. increased control with activation and decreased control with inhibition of an enzyme or group of enzymes. Paradoxical control behaviour occurs widely when enzyme activity is altered by changing Km (if an enzyme is already close to saturation by its substrate), but may also occur with changes in Vmax. when the elasticity to the linking metabolite increases with its concentration (as in some cases of sigmoidal and exponential kinetics or for reactions catalysed by isoenzymes). These findings suggest that enzymes with sigmoidal kinetics may have low control in the absence of activation, but may gain control with activation, and thus have beneficial regulatory properties.
Allosteric Regulation↗
Transthoracic echocardiographic findings in patients with acute retinal arterial obstruction. A retrospective review. Retinal Emboli of Cardiac Origin Group.
OBJECTIVE: To assess the importance of cardio-embolic (emboli of cardiac origin) risk stratification in the cardiac evaluation of patients with acute retinal arterial obstruction. DESIGN: A multicenter retrospective study of patients with acute retinal arterial obstruction who underwent transthoracic echocardiography. SETTINGS: Four North American hospital centers. PATIENTS: One hundred patients with acute retinal artery obstruction in whom transthoracic echocardiography was performed. MAIN OUTCOME MEASURE: Anticoagulation or cardiac surgery based on abnormalities detected on transthoracic echocardiography. Transesophageal echocardiographic results were not evaluated, as they were rarely performed in our centers. Thus, the outcome measure was determined solely by the results of transthoracic echocardiography. RESULTS: Patients were divided into high- and low-risk groups based on their history of cardioembolic risk factors or the presence of a cardiac murmur. Of 67 patients with no risk factors, 41 (61%) had normal echocardiographic study results and 26 (39%) had abnormalities detected, of whom only 1 (1.5%) received anticoagulation or cardiac surgery. The presence of 1 or more cardio-embolic risk factors increased the likelihood for anticoagulation or cardiac surgery 25 times (odds ratio = 25; 95% confidence interval = 3.04-217.02). Although this result is clinically and statistically significant, it is possible that abnormalities missed by transthoracic methods may have been detected by transesophageal technology. CONCLUSIONS: In patients with acute retinal arterial obstruction at low cardioembolic risk, transthoracic echocardiography resulted in anticoagulation or cardiac surgery in 1 (1.5%) of 67 patients. Routine transthoracic echocardiography without follow-up transesophageal echocardiography for patients identified as having abnormalities such as left ventricular hypertrophy or mitral annular calcification and who are at low cardioembolic risk rarely resulted in anticoagulation or cardiac surgery.
Acute Disease↗
Kinetic analysis of changes in activity of heart mitochondrial oxidative phosphorylation system induced by ischemia.
The authors have previously shown that ischemia causes inhibition of the respiratory chain and phosphorylation system, and stimulation of the proton leak of mitochondria isolated from rat heart. It is shown here that the activity of the mitochondrial respiratory chain (after 30 min ischemia, but not after 45 min) and the phosphorylation system are completely restored to the normal level by the addition of exogenous cytochrome c when succinate is used as substrate. Moreover, cytochrome c causes apparent activation of the respiratory chain, the phosphorylation system and the proton leak in normal mitochondria. This can be explained by a fraction of the mitochondrial population lacking cytochrome c and this fraction may increase with ischemia. Experiments on skinned cardiac fibers showed that cytochrome c has no effect on mitochondrial respiration after 15 min ischemia, but the stimulation of respiration by cytochrome c progressively increases when ischemia was prolonged up to 30 min and 45 min, suggesting that the loss of cytochrome c may occur in vivo during the early reversible phase of ischemia. Mitochondria isolated from hearts after 45 min ischemia have a defect in the respiratory chain unrelated to the loss of cytochrome c. These mitochondria have an increased level of Ca2+: 10.05 nmol/mg protein compared to 4.64 nmol/mg in control mitochondria and 4.32 nmol/mg in 30 min ischemic mitochondria. The increase in the proton leak in ischemic mitochondria is mostly reversible by albumin and thus, may be related to an increased level of free fatty acids in ischemic mitochondria.
Animals↗
Vitrectomy in eyes with peripheral retinal angioma associated with traction macular detachment.
PURPOSE: Peripheral angiomas have been associated with epiretinal membranes and traction retinal detachment. The authors investigated the timing, results, and complications of vitreous surgery to remove the retinal traction and treat the peripheral vascular tumor. METHODS: The authors reviewed the results of ten eyes that had undergone vitrectomy for macular pucker and/or traction retinal detachment. These eyes had either preoperative or intraoperative treatment of the peripheral tumor. RESULTS: Patients were followed 4 to 95 months. Six eyes had nonfamilial peripheral acquired retinal hemangioma, three had von Hippel angiomas, and one had multiple large peripheral retinal angiomas associated with extensive retinal telangiectasis. Four eyes received cryotherapy and/or laser photocoagulation 2 to 3 months before surgery. In the remaining six eyes, initial treatment to the peripheral angioma was performed at the time of vitreous surgery. At final follow-up, all eyes were attached without retinal traction. Vision improved in all eyes; six (60%) achieved 20/50 or better visual acuity. Complications included recurrent epiretinal membrane (n=3); nonregressed angiomas (n=3); increased nuclear sclerosis (n=2); and retinal detachment (n=1). CONCLUSION: Vitreous surgery, when applied to epiretinal membranes or traction retinal detachments associated with peripheral vascular tumors, has a good chance of improving vision. Treatment of the hemangioma, before or during vitrectomy, usually results in tumor regression.
Adult↗
Inside-out meniscal repair using zone-specific instruments.
In the last decade, arthroscopic meniscus repair has become established as the treatment of choice for many meniscal lesions previously managed by meniscectomy. Biomechanical and clinical evidence supports meniscus repair for healable tears, especially in adolescents and young adults, while partial meniscectomy is appropriate for most of the remainder. Meniscus repair is a demanding technique that requires the skill of a dedicated arthroscopist. Special suturing tools and techniques often are required, but these are no substitute for appropriate selection and thorough preparation of specific tears that are likely to heal. Complete rehabilitation and a stable knee are required postoperatively to ensure a successful result.
Adult↗
Control and kinetic analysis of ischemia-damaged heart mitochondria: which parts of the oxidative phosphorylation system are affected by ischemia?
We investigated the effects of ischemia on the kinetics and control of mitochondria isolated from normal and ischemic heart. The dependence of the respiratory chain, phosphorylation system and proton leak on the mitochondrial membrane potential were measured in mitochondria from hearts after 0, 30 min and 45 min of in vitro ischemia. Data showed that during the development of ischemia from the reversible (30 min) to the irreversible (45 min) phase, a progressive decrease in activity of the respiratory chain occurs. At the same time an increase in proton leak across the mitochondrial inner membrane was observed. Phosphorylation is inhibited but seems to be less affected by ischemia than respiratory chain or proton leak. Control coefficients of the 3 blocks of reactions over respiration rate were determined in different respiratory states between state 4 and state 3. Ischemia caused the control exerted by the proton leak to increase in state 3 and the intermediate state and caused the control by the phosphorylation system to decrease in the intermediate state. Taken together, these results indicate that the main effects of ischemia on mitochondrial respiration are an inhibition of the respiratory chain and an increase of the proton leak.
Animals↗
Calcium indirectly increases the control exerted by the adenine nucleotide translocator over 2-oxoglutarate oxidation in rat heart mitochondria.
The effect of calcium on the control exerted by the adenine nucleotide translocator over respiration in isolated heart mitochondria was investigated in order to determine whether calcium directly stimulates the translocator. At respiration rates intermediate between states 3 and 4, Ca2+ is shown to increase the control over 2-oxoglutarate oxidation exerted by the adenine nucleotide translocator in rat heart mitochondria. This did not occur when succinate was the respiratory substrate, even though the control exerted by the translocator was substantial, indicating that Ca2+ does not have a direct effect on the adenine nucleotide translocator. Ca2+ increased the uncoupled oxidation rate of 2-oxoglutarate, but not succinate. Using the summation theorem for flux control, the effect of Ca2+ is explained by a shift of the control over respiration rate toward the adenine nucleotide translocator, from the respiratory chain, presumably as the result of the activation of the 2-oxoglutarate dehydrogenase complex.
Adenosine Triphosphate↗
Reversible binding and inhibition of catalase by nitric oxide.
The interactions between nitric oxide (NO), H2O2, and catalase were investigated. H2O2 did not cause detectable breakdown of NO in the absence of catalase, but did cause NO breakdown in the presence of catalase. Catalase bound NO, and NO rapidly and reversibly inhibited catalase with a Ki of 0.18 microM. The significance of these results for NO cytotoxicity is discussed.
Animals↗
Nitric oxide regulates mitochondrial respiration and cell functions by inhibiting cytochrome oxidase.
Nitric oxide (NO) reversibly inhibits mitochondrial respiration by competing with oxygen at cytochrome oxidase. Concentrations of NO measured in a range of biological systems are similar to those shown to inhibit cytochrome oxidase and mitochondrial respiration. Inhibition of NO synthesis results in a stimulation of respiration in a number of systems. It is proposed that NO exerts some of its main physiological and pathological effects on cell functions by inhibiting cytochrome oxidase. Further NO may be a physiological regulator of the affinity of mitochondrial respiration for oxygen, enabling mitochondria to act as sensors of oxygen over the physiological range.
Animals↗
The interactions between nitric oxide and brain nerve terminals as studied by electron paramagnetic resonance.
It has been proposed that nitric oxide (NO) toxicity is due to damage to mitochondrial iron-sulfur centers, resulting in inhibition of mitochondrial respiration and the appearance of an EPR-detectable (g = 2.04) iron-sulfur dinitrosyl complex - Fe(RS)2(NO)2. We show that the addition of nitroprusside (an NO and NO+ donor) to rat brain synaptosomes generates large (> 30 microM) concentrations of EPR-detectable iron-sulfur-dinitrosyl complexes. However, there was no correlation between the size of the g = 2.04 EPR signal and the inhibition of synaptosomal respiration. No significant loss of intensity was seen from the mitochondrial iron-sulfur protein EPR signals. The results are consistent with previous data demonstrating that cytochrome oxidase, not iron-sulfur enzymes, is the primary target for NO inhibition of brain cell respiration (Brown, G.C. and Cooper, C.E. (1994) FEBS Lett. 356, 295-298).
Animals↗
Nitric oxide produced by activated astrocytes rapidly and reversibly inhibits cellular respiration.
Cultured astrocytes, activated to express the inducible form of nitric oxide synthase, produced up to 1 microM nitric oxide (NO) measured by a NO-selective electrode, while non-activated cells produced no detectable NO. The production of NO was associated with an inhibition of cellular respiration, measured simultaneously by an oxygen electrode. The inhibition of respiration was rapidly reversed by inhibiting the NO synthase or by binding the NO with haemoglobin. The respiratory inhibition had an NO, oxygen and substrate dependence consistent with NO-inhibition at cytochrome oxidase. This is the first demonstration that cells can reversibly inhibit mitochondrial respiration via NO production. This inhibition is large and potentially important in a range of pathophysiological conditions.
Animals↗
Diabetic papillopathy. Patient characteristics and fundus findings.
OBJECTIVE: To better define the spectrum of patient characteristics and fundus findings in patients with a presumably unique clinical entity referred to as diabetic papillopathy. DESIGN: Retrospective series. SETTING: A university-based referral practice. METHODS: We retrospectively reviewed the medical records of all diabetic patients with benign, transient disc swelling who were evaluated at our institution from 1986 to 1992. Data pertaining to patient demographics, visual acuity and symptoms, disc and retinal findings, ancillary test results, and clinical course were collected. RESULTS: Twenty-seven eyes of 19 patients met the study definition of diabetic papillopathy. Patients were generally older (mean age, 50 years) and of a broader age range (19 to 79 years) compared with those in prior reports. Two thirds of patients had type II diabetes. Disc swelling was consistently hyperemic and, on average, resolved within 3.7 months. Macular edema was a frequent associated finding (70% of eyes) as was significant capillary nonperfusion (52% of tested eyes). Only four eyes (15%) had final visual acuities of less than 20/50 and each had prominent macular edema. Cup-disc ratio analysis of uninvolved eyes revealed a significantly small physiologic cup. CONCLUSIONS: The clinical profile of diabetic papillopathy can be expanded to include people who are older or have type II diabetes and that affected eyes commonly have macular edema or retinal vascular changes that can adversely affect the visual outcome. Last, a small physiologic cup may represent an anatomic predisposition to the condition.
Adult↗
Communication between the subretinal space and the vitreous cavity in the morning glory syndrome.
BACKGROUND: The aim was to describe a pathogenic mechanism for a rhegmatogenous retinal detachment in a 69-year-old man with the morning glory syndrome. METHODS: During vitreous surgery for a retinal detachment, a membrane was removed that covered the optic disc anomaly and produced traction on the peripapillary retina. A retinal hole was found in tissue lying within the optic cup, and the hole was sealed using a autologous plasma-thrombin mixture. Silicone oil was used for retinal tamponade. RESULTS: A retinal hole in tissue lying within the optic cup provided a fluid pathway between the vitreous cavity and the subretinal space. Following vitrectomy surgery, bubbles of silicone oil passed through the retinal hole into the subretinal space of the macula. CONCLUSION: This case demonstrates that a retinal hole in tissue lying within the optic disc anomaly of the morning glory syndrome provides a communication for fluid between the subretinal space and the vitreous cavity, resulting in a rhegmatogenous retinal detachment. Vitreous replacement with silicone oil resulted in the migration of silicone bubbles into the subretinal space.
Aged↗