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Biomedical subjects

D K Anderson

Publications and source records attributed to D K Anderson.

At least 73 records · Page 4Linked to original sources
PubMed1987

Effects of methylprednisolone and the combination of alpha-tocopherol and selenium on arachidonic acid metabolism and lipid peroxidation in traumatized spinal cord tissue.

Traumatic injury of the spinal cord leads to a series of pathological events that result in tissue necrosis and paralysis. Among the earliest biochemical reactions are hydrolysis of fatty acids from membrane phospholipids, production of biologically active eicosanoids, and peroxidation of lipids. This study examines the effect of agents purported to improve recovery following spinal cord trauma, methylprednisolone sodium succinate (MPSS) and the combination of alpha-tocopherol and selenium (Se), on the posttraumatic alterations of membrane lipid metabolism. Pretreatment with either MPSS or alpha-tocopherol and Se reduced the trauma-induced release of total FFA including arachidonate in the injured spinal cord tissue. In addition, these agents decreased the postinjury levels of prostanoids. Pretreatment with either MPSS or alpha-tocopherol and Se also completely prevented the trauma-induced loss of cholesterol while inhibiting the increase of a cholesterol peroxidation product, 25-hydroxycholesterol. These data suggest that: perturbation of membrane lipid metabolism may contribute to the tissue necrosis and functional deficit of spinal cord injury and MPSS or the combination of alpha-tocopherol and Se may protect injured spinal cord tissue, at least in part, by limiting these posttraumatic membrane lipid changes.

Animals↗
PubMed1987

Hemoglobin potentiates central nervous system damage.

Iron and iron compounds--including mammalian hemoglobins--catalyze hydroxyl radical production and lipid peroxidation. To determine whether hemoglobin-mediated lipid peroxidation might be important in hemorrhagic injuries to the central nervous system (CNS), we studied the effects of purified hemoglobin on CNS homogenates and injected hemoglobin into the spinal cords of anesthetized cats. Hemoglobin markedly inhibits Na/K ATPase activity in CNS homogenates and spinal cords of living cats. Hemoglobin also catalyzes substantial peroxidation of CNS lipids. Importantly, the potent iron chelator, desferrioxamine, blocks these adverse effects of hemoglobin, both in vitro and in vivo. Because desferrioxamine is not known to interact with heme iron, these results indicate that free iron, derived from hemoglobin, is the proximate toxic species. Overall, our data suggest that hemoglobin, released from red cells after trauma, can promote tissue injury through iron-dependent mechanisms. Suppression of this damage by desferrioxamine suggests a rational therapeutic approach to management of trauma-induced CNS injury.

Animals↗
PubMed1987

Evaluation of an intensive methylprednisolone sodium succinate dosing regimen in experimental spinal cord injury.

Beginning 30 minutes after compression trauma of the upper lumbar (L-2) spinal cord, cats were treated with either a high-dose regimen of methylprednisolone (MP) administered as the sodium salt of the 21-succinate ester (Solu-Medrol sterile powder) or the MP vehicle. Animals were randomly assigned to either treatment group (10 cats per group), and all personnel were blind as to which animals received vehicle or drug. The intensive 48-hour dosing regimen was designed to maintain therapeutic tissue levels of MP and consisted of an initial 30 mg/kg intravenous bolus of MP; 2 and 6 hours later additional 15 mg/kg MP doses were administered by intravenous bolus. Immediately following the bolus given at 6 hours, a continuous MP infusion of 2.5 mg/kg/hr was started. The infusion was stopped abruptly at 48 hours with no dose tapering. Animals in the vehicle group received an equivalent volume of MP vehicle. The total MP dose administered over 48 hours was 165 mg/kg. Animals were evaluated weekly for neurological recovery based upon a 12-point functional scale which assessed general mobility, running, and stair-climbing. Mean recovery scores at 1 month after injury (+/- standard error of the mean) were: vehicle group (seven cats) 3.7 +/- 0.9, and MP group (10 cats) 8.7 +/- 0.2; (p less than 0.001). Histological evaluation of the spinal cords revealed a strong negative correlation between neurological recovery and size of the spinal cord cavity at 1 month (r = -0.88). Three of 10 animals in the vehicle group became ill and had to be dropped from the study, whereas all of the 10 MP-treated animals survived in excellent health. The results demonstrate the therapeutic effectiveness and low incidence of side effects associated with an intensive MP dose regimen for treatment of experimental spinal cord injury.

Animals↗
PubMed1986

Thrombin interactions with central nervous system tissue and implications of these interactions.

A monospecific antibody was developed to human alpha-thrombin. This antibody stained neurons but not astrocytes in murine spinal cord cultures incubated with 1-10 nM alpha-thrombin using the avidin-biotin-peroxidase technique. Staining did not occur when the primary or linking antibodies were eliminated, and staining was blocked with hirudin. Preliminary studies showed release of arachidonic acid from the cultures when exposed to thrombin. It was proposed that arachidonate release from the membranes of neurons upon exposure to thrombin was similar to that observed in platelets, for example, by activation of phospholipases. Moreover, prostanoids were formed that could have a deleterious effect on cellular elements in the central nervous system. The potential role of thrombin receptors on neurons was discussed.

Animals↗
PubMed1985

Complete nucleotide sequence of the M RNA segment of Rift Valley fever virus.

The entire M RNA segment of the phlebovirus Rift Valley fever virus (RVFV) has been molecularly cloned and the complete nucleotide sequence determined. The RNA is 3884 nucleotides in length, corresponding to a molecular weight of 1.38 X 10(6), having a base composition of 27.3% A, 25.4% G, 27.2% U, and 20.1% C. Sequences present at the 3' and 5' termini of the molecule are largely complementary for some 51 residues and can form a stable duplex structure when the potential secondary structure of the entire molecule is considered. A single major open reading frame, capable of encoding 1206 amino acids (131,845 Da), was found in the viral-complementary sequence ("positive" polarity). Amino-terminal amino acid sequencing of the purified viral glycoproteins G1 and G2 allowed for the positioning of the coding sequences for these polypeptides within this major open reading frame in the following orientation with respect to the genomic M RNA: 3'-G2-G1-5'. From the predicted amino acid composition of the two mature viral glycoproteins, both were found to have a high cysteine content (G2, 6%; G1, 5%). Sequences within the open reading frame capable of encoding up to 23,000 Da of polypeptide were found in addition to those required for the viral glycoproteins. The potential contribution of these sequences to the coding capacity of the M RNA, viral protein processing, and intracellular protein distribution is discussed.

Amino Acid Sequence↗
PubMed1985

Effects of prenatal stress on differentiation of the sexually dimorphic nucleus of the preoptic area (SDN-POA) of the rat brain.

The present study was designed to determine the effects of prenatal malnutrition or environmental stress on the development of the sexually dimorphic nucleus of the preoptic area (SDN-POA). Pregnant rats were divided into a control group and two treatment groups (immobilization-illumination-heat or environmental stress, and nutritional stress). The two forms of stress were administered during the third trimester of gestation (days 14-20). Male and female offspring were sacrificed at birth, 20, and 60 days postnatally. The cross-sectional area of the SDN-POA was identified under light microscopy and was measured. The data confirm previous studies by showing a significant sex difference in the SDN-POA between control male and female rats. Prenatally stressed males sacrificed 20 and 60 days after birth showed SDN-POA areas 50% smaller than the nuclear areas of control males. The size of the SDN-POA of female offspring, however, was not significantly altered by prenatal treatments.

Animals↗
PubMed1985

Mechanical damage to murine neuronal-enriched cultures during harvesting: effects on free fatty acids, diglycerides, Na+,K+-ATPase, and lipid peroxidation.

The most commonly used procedure to harvest cultured cells from petri dishes is to scrape the cells off the plates with a rubber or Teflon policeman. However, the results reported herein demonstrate that this technique, with its associated mechanical trauma, significantly perturbed cell membranes in neuronal-enriched cultures derived from the ventral half of fetal murine spinal cords. This is evidenced by liberation of free fatty acids and diglycerides, partial inhibition of Na+,K+-ATPase activity, and increased malondialdehyde production. Harvesting the cells by freezing, either on liquid nitrogen or dry ice, significantly attenuated these effects. This important observation indicates that mechanical manipulation of cultured cells during harvesting significantly affects subsequent biochemical analyses, particularly those associated with the cell membrane (e.g., membrane lipid metabolism and assay of intrinsic membrane enzymes).

Animals↗
PubMed1985

Iron-induced lipid peroxidation in spinal cord: protection with mannitol and methylprednisolone.

The ability of the free radical scavenger, mannitol, and the synthetic glucocorticoid, methylprednisolone sodium succinate (MPSS) to reverse the effects of iron catalyzed free radical induced lipid peroxidation was assessed in the feline spinal cord. Ferrous chloride (100 mM) was infused into the gray matter of lumbar spinal cord, the region frozen in situ, removed, and homogenates of the gray matter analyzed for activity of Na+,K+-ATPase and levels of malondialdehyde (MDA). ATPase activity had declined to approximately 30% of control by 2 h after FeCl2 infusion and remained at this level through 24 h. Malondialdehyde values were elevated almost twofold at 2 h. Mannitol essentially reversed the effects of FeCl2 infusion on Na+,K+-ATPase activity and MDA production. These results may implicate the hydroxyl radical (. OH), or an oxidizing species with . OH-like reactivity, as the initiating radical species in this model of lipid peroxidation. Similarly, MPSS prevented the decline in spinal cord Na+,K+-ATPase activity and rise in MDA levels that were induced by FeCl2 infusion. This demonstrated that at the dosage levels used in this study, MPSS was an effective antioxidant. This finding provides presumptive evidence suggesting that, at least in experimental animals, the effectiveness of MPSS in preventing the tissue necrosis and paralysis that is the sequelae of spinal cord trauma may reside, in part, in the capacity of this glucocorticord to quench peroxidative reactions in the injured tissue.

Animals↗
PubMed1985

Spinal cord injury and protection.

Subsequent to traumatic injury of the spinal cord, a series of pathophysiological events occurs in the injured tissue that leads to tissue destruction and paraplegia. These include hemorrhagic necrosis, ischemia, edema, inflammation, neuronophagia, loss of Ca2+ from the extracellular space, and loss of K+ from the intracellular space. In addition, there is trauma-initiated lipid peroxidation and hydrolysis in cellular membranes. Both lipid peroxidation and hydrolysis can damage cells directly; hydrolysis also results in the formation of the biologically active prostaglandins and leukotrienes (eicosanoids). The time course of membrane lipid alterations seen in studies of antioxidant interventions suggests that posttraumatic ischemia, edema, inflammation, and ionic fluxes are the result of extensive membrane peroxidative reactions and lipolysis that produce vasoactive and chemotactic eicosanoids. A diverse group of compounds has been shown to be effective in ameliorating spinal cord injury in experimental animals. These include the synthetic glucocorticoid methylprednisolone sodium succinate (MPSS); the antioxidants vitamin E, selenium, and dimethyl sulfoxide (DMSO); the opiate antagonist naloxone; and thyrotropin-releasing hormone (TRH). With the exception of TRH, all of these agents have demonstrable antioxidant and/or anti-lipid-hydrolysis properties. Thus the effectiveness of these substances may lie in their ability to quench membrane peroxidative reactions or to inhibit the release of fatty acids from membrane phospholipids, or both. Whatever the mode of action, early administration appears to be a requirement for maximum effectiveness.

Animals↗
PubMed1985

Membrane lipid changes in laminectomized and traumatized cat spinal cord.

Free fatty acid (FFA), diacylglycerol (acyl2Gro), icosanoid, phospholipid, and cholesterol levels were measured in samples of cat spinal cord (L2) that were frozen in situ with vertebrae intact, at various times after laminectomy, and at various times after laminectomy with compression trauma to the spinal cord. Tissue samples either were grossly dissected into gray and white portions prior to FFA and acyl2Gro analysis or were used whole for the other lipid types. Gray matter total FFA and acyl2Gro values were abnormally high in samples frozen with vertebrae intact and in those frozen 10 min after laminectomy. This indicates that the surgical procedures resulted in some perturbation of spinal cord lipid metabolism. If the experimental animals were allowed to recover for 90 min after laminectomy, the gray matter FFA and acyl2Gro levels were greatly reduced. Compression of the spinal cord with a 170-g weight for 1, 3, or 5 min (following 90 min of recovery after laminectomy) caused significant elevations of total FFA, acyl2Gro, icosanoids, and phosphatidic acid and significant decreases in ethanolamine plasmalogens and cholesterol. Among the total FFA, arachidonic acid was found to have the largest relative increase. Comparisons of gray and white matter demonstrate that, in general, changes in white matter FFA and acyl2Gro were similar to those seen in gray matter. However, the increases in white matter levels of FFA and acyl2Gro were delayed, occurring after the elevations in gray matter. For some FFA (e.g., arachidonate), the rise in white matter occurred as gray matter levels were decreasing. This suggests that the initial alteration in spinal cord lipid metabolism after trauma was in gray matter but, with time, spread radially into white matter.

Animals↗
PubMed1985

The degradation of phospholipids, formation of metabolites of arachidonic acid, and demyelination following experimental spinal cord injury.

Spinal cord injury has been studied using a cat compression model. Very early changes in lipid metabolism were found that compromise the integrity of the plasma membrane and decrease the activities of ATPases. Up to 18% of the ethanolamine plasmalogens are lost, with very marked elevations of the free fatty acids, arachidonic acid, diacylglycerols, prostaglandins, thromboxanes, and leukotrienes. These changes result in edema, inflammation, necrosis of oligodendroglia, demyelination, and paralysis.

Animals↗
PubMed1985

Lipid hydrolysis and peroxidation in injured spinal cord: partial protection with methylprednisolone or vitamin E and selenium.

Compression trauma of the cat spinal cord induces a very rapid alteration in the lipid metabolism of cellular membranes, including lipid hydrolysis with release of fatty acids including arachidonate, production of biologically active eicosanoids, and loss of cholesterol. This disturbance of cellular membranes can directly damage cells and can lead to the secondary development of tissue ionic imbalance, ischemia, edema, and inflammation with neuronophagia. Pretreatment with either the synthetic glucocorticoid methylprednisolone sodium succinate (MPSS) or the antioxidants vitamin E and selenium (Se) completely prevented the loss of cholesterol and partially inhibited lipolysis and prostanoid production. Treatment with MPSS significantly reduced the postinjury tissue necrosis and paralysis. Preliminary evidence indicates that pretreatment with vitamin E and Se also protected against the effects of spinal cord injury (SCI). We speculate that the ability of these agents to preserve function after SCI may, in part, reside in their capacity to limit the trauma-induced changes in lipid metabolism.

Animals↗
PubMed1985

Immunological studies on the mechanism of halothane-induced hepatotoxicity: immunohistochemical evidence of trifluoroacetylated hepatocytes.

The fulminant hepatotoxicity caused by halothane has been thought to have an immunological basis because this toxicity occurs most often after repeated administration of halothane and because sera from patients recovering from severe halothane hepatotoxicity contain antibodies that bind to the surface membranes of hepatocytes of rabbits treated with halothane. In order to determine whether the major reactive metabolite of halothane, trifluoroacetyl halide, covalently binds to hepatocytes, we have developed specific and sensitive peroxidase enzyme-linked immunosorbent assays and an indirect immunofluorescence staining method for identifying trifluoroacetylated (TFA)-hepatocytes. Liver sections prepared from rats at 4 hr after halothane administration were stained preferentially in the centrilobular region with anti-TFA serum whereas livers of control rats showed no staining. The specificity of the assay for the TFA group was confirmed by the complete inhibition of the staining with 200 microM N-epsilon-TFA-L-lysine in the diluted antiserum. On the other hand, 2 mM halothane or L-lysine did not inhibit this staining. Moreover, treatment of rats with deuterated halothane resulted in significantly less staining than did halothane. At 24 hr after halothane administration, hepatocytes isolated and stained by indirect immunofluorescence showed a linear and granular pattern on their surface membranes. These results indicate that trifluoroacetyl halide either reacts directly with constituents of the plasma membranes or with other cellular components which become incorporated into the plasma membranes.

Animals↗
PubMed1983

Granulosis viruses, with emphasis on the GV of the Indian meal moth, Plodia interpunctella.

The granulosis viruses and nuclear polyhedrosis viruses are being considered for use as biological insecticides for control of their insect hosts. Many of these insect species, which include some of the most serious pests of agriculture and forests, have become difficult to control because they have developed resistance to chemical insecticides. Several laboratory and field studies have demonstrated that the baculoviruses (GV and NPV) are promising alternatives to chemicals for the control of economically important insects. These viruses are highly virulent, selective, and stable, and the impact on the environment following their application is minimal. A decision concerning the application of baculoviruses to stored grain and field crops must be based upon a prudent consideration of the benefits to be obtained and the potential risks of their use. Such decisions should be made only after consideration of the physical, chemical, and biological properties of these viruses. In addition, methods must be developed for the unequivocal identification of these viruses, and their effects on nontarget species at the cellular and molecular levels must be investigated. This can best be accomplished if a sufficient body of knowledge regarding the molecular properties of these viruses and their infection process is accumulated by an extensive quantitative approach. Much of this knowledge is lacking because, prior to their consideration for use as insecticides, the baculoviruses appeared to have little medical or economic importance. As a result, interest in studying them was limited. It has become obvious that the molecular properties of these viruses must be investigated if full advantage is to be taken of using them as insect control agents, and if present and future problems concerning their use as insecticides are to be handled properly. Fundamental research on the biochemical and biophysical properties of baculoviruses has concentrated mainly on a variety of nuclear polyhedrosis viruses (Harrap, 1972a,b; Harrap et al., 1977; Summers and Smith, 1975a,b; Arif and Brown, 1975). Much of this progress can be attributed to tissue culture-host cell systems available for the NPVs. The in vitro host system(s) has allowed insect virologists to make phenomenal strides in understanding the cellular and molecular events of virus infection, and, in addition, to enter the era of biochemical sophistication in which animal virology is found at present.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Neuronophagia by leukocytes in experimental spinal cord injury.

Experimental spinal cord injury was produced in cats by compression trauma. The major histologic features in the first 24 hours following injury included hemorrhagic necrosis, edema, and acute inflammation of gray and white matter. Neutrophilic leukocytes (NL) were apparent in the walls of and adjacent to veins and venules within four hours of injury, but large numbers of NL were not observed in tissue until eight to 24 hours. Acute inflammation was especially prominent in gray matter, and NL frequently surrounded and phagocytized neuronal somata. Large numbers of NL and neuronophagia by leukocytes were evident only in areas of hemorrhage. The role of blood in producing the acute inflammatory response and in generating chemotactic factors responsible for neuronophagia is incompletely understood. Neutrophilic leukocytes, in addition to their response as phagocytes, release histolytic enzymes, reactive species of oxygen, and proinflammatory factors which lead to further tissue necrosis and inflammation.

Animals↗