Conductive, interstitial hyperthermia: a new modality for treatment of intracranial tumors.
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Brain Neoplasms↗
Biomedical subjects
C F Babbs
Publications and source records attributed to C F Babbs.
Detection and quantitation of hydroxyl radical using dimethyl sulfoxide as molecular probe.
Generation of clearly harmful amounts of hydroxyl radicals in biological systems can be studied using DMSO as a molecular probe. DMSO is oxidized by HO. to form the stable, nonradical compound methanesulfinic acid, which is not normally found in living systems and which can be easily extracted from tissue and measured spectrophotometrically. The present method provides a simple, inexpensive assay for methanesulfinic acid in biological materials. As little as 10 nmol of sulfinate can be detected, and interference from diverse biological compounds is minimal. Additionally, there is no interference from a large excess of dimethyl sulfoxide, which is necessary if the assay is to be applied directly to tissues pretreated with DMSO. When straightforward cleanup procedures are utilized, there is minimal interference from glutathione or sulfate, and potentially troublesome interference from detergentlike substances can usually be minimized. Owing to its relative specificity for sulfinic acids at acid pH, the diazonium coupling reaction can thus be exploited to provide an efficient and inexpensive means of detecting methanesulfinic acid in DMSO-pretreated biological materials. The results provide a direct chemical means for measuring cumulative HO. generation.
Animals↗
Hydroxyl radical generation by postischemic rat kidney slices in vitro.
To quantitate the formation of hydroxyl radicals (HO.) in ischemia and reoxygenation, dimethyl sulfoxide (DMSO) was added to "trap" evolving HO. in normal, in ischemic, and in ischemic and reoxygenated rat kidney slices, incubated in short-term organ culture in vitro. Hydroxyl radical generation was measured as the accumulation of the specific product of DMSO oxidation by HO., methane sulfinic acid (MSA) in the kidney tissue and surrounding medium using a new colorimetric assay. A mean difference of 7 nmol cumulative HO./gram tissue was detected in rat kidney slices subjected to ischemia and reoxygenation. This amount of HO. generation was not significantly greater than that found in nonischemic or in ischemic but not reoxygenated control tissues, and does not appear to represent the highly toxic burst of HO. radicals implied in current theoretical discussions of reperfusion injury. However, the addition of EDTA chelated iron (1:1) to the incubation medium led to marked postischemic HO. generation. We conclude that clearly toxic numbers of HO. radicals are not formed during reoxygenation in rat kidney slices, either because there is insufficient iron, because only a small fraction of cells in the kidney tissue make oxygen radicals, or because cellular defenses against HO. formation are more powerful than currently appreciated.
Animals↗
Simulation of free radical reactions in biology and medicine: a new two-compartment kinetic model of intracellular lipid peroxidation.
To explore mechanisms of free radical reactions leading to intracellular lipid peroxidation in living systems, we developed a computational model of up to 109 simultaneous enzymatic and free radical reactions thought to be involved in the initiation, propagation, and termination of membrane lipid peroxidation. Rate constants for the various reactions were obtained from the published literature. The simulation model included a lipid membrane compartment and an aqueous cytosolic compartment, between which various chemical species were partitioned. Lipid peroxidation was initiated by the iron-catalyzed, superoxide-driven Fenton reaction. A "C" language computer program implemented numerical solution of the steady-state rate equations for concentrations of nine relevant free radicals. The rate equations were integrated by a modified Euler technique to describe the evolution with time of simulated concentrations of hydrogen peroxide, ferric and ferrous iron, unsaturated lipid, lipid hydroperoxides, superoxide anion, and biological antioxidants, including SOD and catalase. Initial results led to significant insights regarding mechanisms of membrane lipid peroxidation: 1. segregation and concentration of lipids within membrane compartments promotes chain propagation; 2. in the absence of antioxidants computed concentrations of lipid hydroperoxides increase linearly about 40 microM/min during oxidative stress; 3. lipid peroxidation is critically dependent upon oxygen concentration and the modeled dependence is similar to the experimental function; 4. lipid peroxidation is rapidly quenched by the presence of Vitamin E-like antioxidants, SOD, and catalase; 5. only small (1 to 50 microM) amounts of "free" iron are required for initiation of lipid peroxidation; 6. substantial lipid peroxidation occurs only when cellular defense mechanisms have been weakened or overcome by prolonged oxidative stress, hence understanding of the balance between free radical generation and antioxidant defense systems is critical to the understanding and control of free radical reactions in biology and medicine.
Antioxidants↗
Free radicals and the etiology of colon cancer.
This hypothesis paper reviews diverse evidence suggesting that intracolonic production of oxygen radicals may play a role in carcinogenesis. The hypothesis began to evolve when the author made the chance discovery that 1/10,000 dilutions of feces generated detectable quantities of highly reactive hydroxyl radicals (HO.). The rate of HO. formation, detected using DMSO as a molecular probe, was quite remarkable, corresponding to that which would be produced by over 10,000 rads of gamma irradiation per day, absorbed in the periphery of the fecal mass adjacent to the mucosa. The relatively high concentrations of iron in feces, together with the ability of bile pigments to act as iron chelators that support Fenton chemistry, may very well permit efficient HO. generation from superoxide and hydrogen peroxide produced by bacterial metabolism. Such free radical generation in feces could provide a missing link in our understanding of the etiology of colon cancer: the oxidation of procarcinogens either by fecal HO., or by secondary peroxyl radicals (ROO.) to form active carcinogens or mitogenic tumor promotors. Intracolonic free radical formation may explain the high incidence of cancer in the colon and rectum, compared to other regions of the GI tract, as well as the observed correlations of a higher incidence of colon cancer with red meat in the diet, which increases stool iron, and with excessive fat in the diet, which may increase the fecal content of procarcinogens and bile pigments.
Animals↗
Association of magnesium deficiency with the blood pressure-lowering effects of calcium.
The role of dietary calcium and magnesium in the development of hypertension was studied in nine groups, each consisting of nine spontaneously hypertensive rats aged 8-31 weeks. The animals were fed AIN 76A semi-purified diets varying in calcium (0.075, 0.5 and 2.5%) and magnesium (0.01, 0.05 and 0.75%) concentrations according to a 3 x 3 factorial design. Dietary calcium and systolic blood pressure were inversely related, significantly (P less than 0.05) after 12 weeks. Total and ultrafilterable serum calcium concentrations were also significantly negatively correlated with blood pressure (r = -0.46; P = 0.001 and r = -0.57; P = 0.001, respectively). Repeated measures analysis of variance indicated that dietary magnesium had no effect on systolic blood pressure, and no calcium x magnesium interaction on blood pressure was observed. Signs of magnesium deficiency, calcium deposits in the kidneys, and histological lesions were observed in groups on a high-calcium diet receiving normal and low levels of magnesium. Thus a lowering of blood pressure by calcium supplementation, without concomitant magnesium supplementation, was accompanied by biochemical and histological abnormalities in this animal model.
Animals↗
Theoretical basis for controlling minimal tumor temperature during interstitial conductive heat therapy.
This paper describes simulation of steady-state intratumoral temperatures achieved by a simple modality of local heat therapy: interstitial treatment with parallel arrays of warmed, conductive heating elements. During "conductive heating" power is directly deposited only in the interstitial probes. Adjacent tissue is warmed by heat conduction. Simulations of interstitial conductive heating involved solution of the bioheat transfer equation on a digital computer using a finite difference model of the treated tissue. The simulations suggest that when the complete temperature distributions for conductive interstitial hyperthermia are examined in detail, substantial uniformity of the temperature distributions is evident. Except for a thin sleeve of tissue surrounding each heating element, a broad, flat central valley of temperature elevation is achieved, with a well defined minimum temperature, very close to modal and median tissue temperatures. Because probes are inserted directly in tumor tissue, the thin sleeve of overheated tissue would not be expected to cause normal tissue complications. The temperature of the heated probes must be continuously controlled and increased in the face of increased blood flow in order to maintain minimum tumor temperature. However, correction for changes in blood flow is possible by adjusting probe temperature according to a feedback control scheme, in which power dissipation from each probe is the sensed input variable. Conductive interstitial heating with continually controlled probe temperature deserves investigation as a technique for local hyperthermia therapy.
Computer Simulation↗
Quantitative effects of iron chelators on hydroxyl radical production by the superoxide-driven fenton reaction.
Iron bound to certain chelators is known to promote the conversion of superoxide radicals (O2-) to hydroxyl radicals (HO.) by the superoxide-driven Fenton reaction. The production of HO. by various iron chelates was studied using the reaction of dimethyl sulfoxide and HO. to produce methane sulphinic acid. Methane sulphinic acid was quantified by use of a simple colorimetric assay and used to determine the amounts of HO. produced. Superoxide was generated from 200 microM hypoxanthine and 0.05 U/ml xanthine oxidase in the presence of 0-100 microM iron and 100 microM of each chelator. The results of this preliminary investigation illustrate that, at physiological pH, the superoxide-driven Fenton reaction is significantly promoted by iron chelated to EDTA, nitrilotriacetate, and citrate, but is not promoted by the other anions studied.
Chemical Phenomena↗
Hyperthermia catheter implantation and therapy in the brain. Technical note.
For the treatment of malignant gliomas, a technique for implanting hyperthermia catheters was developed that utilized a stereotactic template and head-stabilization frame mounted on a computerized tomography (CT) scanner. Computerized tomography scans were used to measure tumor dimensions and to determine the number, implantation depths, and active heating lengths of the catheters, which were implanted through twist-drill holes while the patient was in the CT room. Heat was subsequently delivered via implanted catheters using a computer-controlled hyperthermia system, which partially compensates for heterogeneous and time-varying tumor blood flow.
Brain Neoplasms↗
Changes in expired end-tidal carbon dioxide during cardiopulmonary resuscitation in dogs: a prognostic guide for resuscitation efforts.
Expired end-tidal carbon dioxide (PCO2) measurements made during cardiopulmonary resuscitation have correlated with cardiac output and coronary perfusion pressure when wide ranges of blood flow are included. The utility of such measurements for predicting resuscitation outcome during the low flow state associated with closed chest cardiopulmonary resuscitation remains uncertain. Expired end-tidal PCO2 and coronary perfusion pressures were measured in 15 mongrel dogs undergoing 15 min of closed chest cardiopulmonary resuscitation after a 3 min period of untreated ventricular fibrillation. In six successfully resuscitated dogs, the mean expired end-tidal PCO2 was significantly higher than that in nine nonresuscitated dogs only after 14 min of cardiopulmonary resuscitation (6.2 +/- 1.2 versus 3.4 +/- 0.8 mm Hg; p less than 0.05). No differences in expired end-tidal PCO2 values were found at 2, 7 or 12 min of cardiopulmonary resuscitation. A significant decline in end-tidal PCO2 levels during the resuscitation effort was seen in the nonresuscitated group (from 6.3 +/- 0.8 to 3.4 +/- 0.8 mm Hg; p less than 0.05); the successfully resuscitated group had constant PCO2 levels throughout the 15 min of cardiac arrest (from 6.8 +/- 1.1 to 6.2 +/- 1.2 mm Hg). Changes in expired PCO2 levels during cardiopulmonary resuscitation may be a useful noninvasive predictor of successful resuscitation and survival from cardiac arrest.
Animals↗
Scatchard analysis of methane sulfinic acid production from dimethyl sulfoxide: a method to quantify hydroxyl radical formation in physiologic systems.
A major impediment to the confirmation of free radical mechanisms in pathogenesis is a lack of direct, chemical evidence that oxygen centered free radicals actually arise in living tissues in quantities sufficient to cause serious damage. This investigation was conducted to validate the use of dimethyl sulfoxide (DMSO) as a quantitative molecular probe for the generation of hydroxyl radicals (HO.) under physiologic conditions. Reaction of HO. with DMSO produces methane sulfinic acid (MSA) as a primary product, which can be detected by a simple colorimetric assay. To develop a method for estimating total HO. production, we studied two model systems: the superoxide driven Fenton reaction in vitro, using xanthine oxidase as the source of superoxide, and a computer model of Fenton chemistry. Measured MSA production both in vitro and in the computer model was a predictable function of the concentrations of DMSO and competing scavengers of HO., according to the principle of competition kinetics. Both experimental results and model calculations showed that Scatchard analysis may be used to infer total HO. generation, despite the presence of scavengers other than DMSO, such as mannitol. Thus, methane sulfinic acid production from DMSO holds promise as an easily measured marker for HO. formation in biologic systems pretreated with DMSO, and Scatchard analysis of repeated experiments with varying DMSO concentrations can yield an estimate of total HO. generation.
Colorimetry↗
Effect of oxygen concentration on the formation of malondialdehyde-like material in a model of tissue ischemia and reoxygenation.
This study was conducted to explore the functional relationship between oxygen concentration during tissue reoxygenation after ischemia and the extent of postischemic lipid peroxidation, an indicator of reoxygenation injury. Excised rat liver or kidney tissue was rendered ischemic for 1 h at 37 degrees C, minced into 1 mm3 fragments, and then reoxygenated for 1 h in flasks of buffered salt solution containing various amounts of oxygen. Production of malondialdehyde-like material (MDA) was measured to indicate lipid peroxidation. MDA production was minimal at oxygen tensions less than 10 mmHg, increased sharply from 10 to 50 mmHg, and plateaued at approximately 100 mmHg. A similar functional relationship was produced by a simple mathematical model of free radical mediated lipid peroxidation in biological membranes, suggesting that MDA production is indeed caused by free radical oxidation of membrane phospholipids and that the oxygen effect is governed by simple competition between chain propagation and chain termination reactions within the membrane. These experimental and analytical results confirm that relatively low concentrations of oxygen are sufficient to produce oxidative damage in post-ischemic tissues.
Animals↗
Lethal hydroxyl radical production in paraquat-treated plants.
Bipyridinium herbicides, including paraquat and diquat, are believed to act by generating highly reactive, oxygen-centered free radicals within chloroplasts when treated plants are exposed to sunlight. This hypothesis has not yet been confirmed by direct chemical measurements of specific free radicals. We studied paraquat-treated plants using a new method able to detect and quantify formation of highly reactive and deleterious hydroxyl radicals (HO(*)), in which dimethyl sulfoxide (DMSO) is used as a molecular probe. DMSO is oxidized by HO(*) to form the stable, nonradical compound, methane sulfinic acid, which can be easily extracted from plant tissue and measured spectrophotometrically. Initial experiments revealed formation of extraordinary numbers of hydroxyl radicals in light-exposed, paraquat + DMSO-treated plants, equivalent at least to the cumulative number of HO(*) radicals per gram of fresh tissue that would be produced by 10,000 rads of gamma irradiation. This appears to be the greatest production of hydroxyl radicals yet observed in a biological system and is quite sufficient to explain the rapid death of top growth in paraquat-treated plants.
Journal Article↗
Dietary magnesium does not affect blood pressure in spontaneously hypertensive rats.
To determine the therapeutic effectiveness of dietary magnesium in the treatment of established hypertension, 21 male spontaneously hypertensive rats were fed altered levels of magnesium oxide from 17 to 29 weeks of age. The rats were divided into three groups of approximately equal mean baseline systolic blood pressures and fed AIN 76A purified diets containing magnesium at 0.01% (low), 0.05% (normal), and 0.40% (high) levels. Mean systolic blood pressures in the conscious SHR during the 12 week period and terminal direct blood pressures under anesthesia were not significantly different among treatment groups. Total and ultrafilterable serum magnesium concentrations reflected dietary magnesium intake. Total and ultrafilterable serum calcium levels were significantly higher (p less than 0.05) in the low magnesium-fed SHR. Histopathologic alterations indicative of aging did not differ among treatment groups. Therefore, in spite of altered serum mineral status, blood pressure and histopathology were not affected by dietary magnesium.
Animals↗
The post treatment experiment: an operational definition of reperfusion injury.
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Allopurinol↗
A rapid, widely applicable screen for drugs that suppress free radical formation in ischemia/reperfusion.
Substantial injury can occur during reoxygenation of previously ischemic tissue in many experimental models, as the result of the generation of oxygen-derived free radicals. To test the antiradical activity of potentially protective compounds in this setting, we developed a simple screening system, applicable to fresh biopsy specimens, in which warm ischemia and reoxygenation of excised tissue are performed in vitro. Tissue production of malondialdehyde (MDA) equivalents is used as a nonspecific-but-sensitive marker of oxygen radical damage. Test compounds with putative antiradical activity are added prior to the reoxygenation phase, and their ability to suppress MDA production is an index of activity in preventing reoxygenation injury. Comparison with ischemic but not reoxygenated controls confirms the oxygen-dependent nature of the effect. Standard positive controls of known effective agents, such as butylated hydroxytoluene or deferoxamine, provide a reference for the activity of the test compound. The method is applicable to surgical biopsy specimens in veterinary and human medicine.
Animals↗
The effectiveness of postischemic oxypurinol administration upon myocardial function in the isolated rat heart.
The Langendorff isolated rat heart preparation was used to determine the effect of oxypurinol, a xanthine oxidase inhibitor, on myocardial function when administered during reperfusion after 30 min of warm ischemia. Twenty rats were randomly sorted into 2 groups of 10, and an isolated heart preparation made from each rat. The isolated hearts were perfused for 15 min with a modified Krebs-Henseleit solution to permit stabilization of the preparation. Each heart was then subjected to 30 min of total ischemia at 37 degrees C followed by 40 min of reperfusion with either saline-treated perfusate or oxypurinol-treated perfusate (1.3 mM). The maximum power produced and the preload required to produce maximum power were both determined prior to ischemia and every 10 min after ischemia during 40 min of reperfusion. The saline-treated group, but not the oxypurinol-treated group, showed significantly less maximum power output at all testing times during reperfusion compared to the preischemic value (P less than 0.05). There was a significantly greater maximum power output (P less than 0.02) in the oxypurinol-treated group compared to the saline-treated group after 20, 30, and 40 min of reperfusion. There were no differences within either group, or between groups, for the preload required to produce maximum power at any of the testing times. Ultrastructural examination of myocardium after reperfusion showed severe mitochondrial and myofibrillar disruption in the saline-treated group but not in the oxypurinol-treated group. We conclude that oxypurinol administered following 30 min of total ischemia at the onset of reperfusion, can preserve myocardial function during the early reperfusion period in the isolated rat heart.
Animals↗
Myocardial perfusion pressure: a predictor of 24-hour survival during prolonged cardiac arrest in dogs.
Myocardial perfusion pressure, defined as the aortic diastolic pressure minus the right atrial diastolic pressure, correlates with coronary blood flow during cardiopulmonary resuscitation (CPR) and predicts initial resuscitation success. Whether this hemodynamic parameter can predict 24-h survival is not known. We examined the relationship between myocardial perfusion pressure and 24-h survival in 60 dogs that underwent prolonged (20 min) ventricular fibrillation and CPR. Forty-two (70%) animals were initially resuscitated and 20 (33%) survived for 24 h. Myocardial perfusion pressure was significantly greater when measured at 5, 10, 15 and 20 min of ventricular fibrillation in the resuscitated animals than in the non-resuscitated animals (P less than 0.01). Likewise, the myocardial perfusion pressure was also greater in the animals that survived 24 h than in animals that were resuscitated, but died before 24 h (P less than 0.02). Myocardial perfusion pressure measured after 10 min of CPR was 11 +/- 2 mmHg in animals never resuscitated, 20 +/- 3 mmHg in those resuscitated that died before 24 h and 29 +/- 2 mmHg in those that survived 24 h (P less than 0.05). A myocardial perfusion pressure at 10 min of CPR of 20 mmHg or less is an excellent predictor of poor survival (negative predictive value = 96%). Myocardial perfusion pressure is a useful index of CPR effectiveness and therefore may be a useful guide in helping to optimize resuscitation efforts.
Animals↗