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Biomedical subjects

M S Baker

Publications and source records attributed to M S Baker.

At least 73 records · Page 4Linked to original sources

Estimating the treatment costs of breast and lung cancer.

The Continuous Medicare History Sample File (CMHSF) was used to derive an estimate of the lifetime direct medical expenses attributable to two chronic diseases, lung cancer and female breast cancer. These two cancers are the leading cancer causes of death in men and women in the United States. They inflict large costs on the population, both direct and indirect, but the costs have been difficult to measure. The primary obstacle to quantification is the intermittent and long-term nature of treatment for these diseases. A complete record of expenses cannot usually be obtained from one source, however, a review of all the national health surveys, as well as the Medicare statistical files identified the CMHSF, which is maintained by the Health Care Financing Administration in a format suitable for calculation of cumulative medical expenses. Some of the pertinent features of the CMHSF include the following: 1) it is a nationally representative sample of the Medicare population, 2) it is longitudinal covering an 8-year period from 1974 to 1981, 3) it captures the majority of medical expenses for each enrollee, and 4) it can be linked to other national data bases such as the National Death Index. Charges for three phases of cancer treatment were derived from the file: initial therapy, maintenance care, and terminal care. A method is described for computing the present value of life-time treatment costs from the phase-specific charges. The lifetime cost of treating breast cancer in 1984 dollars is $36,926 and lung cancer is $12,510.

Aged↗

Medical aspects of Persian Gulf operations: environmental hazards.

Deployment of troops to the countries surrounding the Persian Gulf will result in exposure to a unique and dangerous environment. The austere and hostile environment is marked by extremes of temperature, dangerous snakes and scorpions, and hazardous marine conditions, in addition to the problems that will be faced by those potentially in combat. Proper education and training prior to deployment, reinforcement by the leadership, and common sense prevention measures will prevent most environmental casualties from occurring.

Animals↗

Medical aspects of Persian Gulf operations: serious infectious and communicable diseases of the Persian Gulf and Saudi Arabian Peninsula.

The countries surrounding the Persian Gulf are remarkable for the variety of infectious and contagious diseases that will affect those deployed to this area. In addition to the common gastrointestinal problems often seen in deployed troops, they will be exposed to such unusual problems as malaria, schistosomiasis, leishmaniasis, and rabies. Medical personnel will need to consider diseases that they have never before treated or diagnosed, and will have to educate their troops regarding control of vectors, avoidance of exposure, and personal hygiene and sanitation. Proper predeployment vaccination, use of appropriate prophylaxis, and use of countermeasures such as insect repellent will keep the spread of disease minimal.

Diarrhea↗

Inhibition of cancer cell urokinase plasminogen activator by its specific inhibitor PAI-2 and subsequent effects on extracellular matrix degradation.

Isotopically labeled [( 3H]serine, [3H]proline, and [35S]sulfate) subendothelial cell basement membranes were used to determine the role of urokinase plasminogen activator (uPA) and its specific inhibitor plasminogen activator inhibitor 2 (PAI-2) in colon cancer cell extracellular matrix degradation. Recombinant PAI-2 irreversibly inhibited low and high molecular weight purified human uPA in addition to both colon cancer cell-associated and secreted uPA, particularly if pro-uPA had been preactivated. Two selected lines (COLO394 and LIM1215) preferentially degraded differently labeled matrices in a time- and plasminogen-dependent manner. This process was inhibitable by PAI-2 in the medium at levels which suggested that some degree of "shielding" of cell surface uPA from inhibitor occurred. The ability of PAI-2 to regulate the invasive phenotype of cells which express cell surface or receptor-bound uPA is discussed.

Cell Line↗

Plasminogen activator inhibitor 2 (PAI-2) is not inactivated by exposure to oxidants which can be released from activated neutrophils.

Purified recombinant human monocyte plasminogen activator inhibitor 2 (PAI-2) retained inhibitory activity after exposure to a number of oxidants, including hypochlorite anion (OCl-), chloramine-T (CT) and hydrogen peroxide (H2O2). Analysis of PAI-2 exposed to oxidants by gel filtration chromatography and SDS-PAGE indicated that although the protein could no longer be detected by silver staining, this was not due to fragmentation of the PAI-2 molecule. The sensitivity of a number of serine protease inhibitors (serpins), (eg. alpha 1 proteinase inhibitor (alpha 1PI) and plasminogen activator inhibitor 1 (PAI-1] to oxidative inactivation has been attributed to oxidation of reactive site methionine residues and/or tertiary structural modifications. The relevance of these phenomena and the potential for PAI-2 to be used as a therapeutic inhibitor of urokinase (uPA)-dependent proteolysis during inflammation and tumour metastasis is discussed.

Amino Acid Sequence↗

Depolymerization of synovial fluid hyaluronic acid (HA) by the complete myeloperoxidase (MPO) system may involve the formation of a HA-MPO ionic complex.

Gel filtration analysis (Sephacryl S-1000) indicated that the Mr of purified equine synovial cell culture 3H-hyaluronic acid (HA) (Mr greater than 1.67 x 10(7) Da) decreased in a concentration dependent manner after exposure to hypochlorite (OCl-). Both high (equine) and medium (human, Mr = 5.5 x 10(5) Da) molecular weight HA were cleaved by the complete myeloperoxidase system (MPO/H2O2/Cl-). Purified human neutrophil myeloperoxidase (MPO) bound tightly to HA-Sepharose and we suggest that this is due to a strong ionic interaction between HA and MPO. The formation of such a complex did not disturb MPO activity. The significance of these results in relation to our previous studies concerning the reduction in viscosity and potential cleavage of HA by the product of the MPO/H2O2/Cl- system is discussed.

Cells, Cultured↗

The acutely injured patient.

This article reviews the examination techniques and priorities for an injured patient. The format can be tailored to both the field setting and the hospital. Learning a concise method of examination and treatment is basic to trauma care and helps ensure that life-threatening injuries are not overlooked.

Critical Care↗

Recognition of vascular injury in the trauma patient.

Medical personnel should be able to recognize vascular injuries. Knowing the key signs of ischemia, namely pallor, pulselessness, pain, paresis, and paresthesia and the soft signs of vascular injury will help to prevent limb loss.

Blood Vessels↗

The inhibitory action of oxygen radical scavengers on proteinuria and glomerular heparan sulphate loss in the isolated perfused kidney.

The perfused isolated kidney is a partial ischemic system that is characterised by glomerular proteinuria and release of glomerular heparan sulfate. Metabolic changes associated with the levels of glutathione, xanthine oxidase and glyceraldehyde 3-dehydrogenase indicated that oxygen radical metabolites were being produced during the perfusion. We have demonstrated that a mixture of oxygen metabolite scavengers containing mannitol, superoxide dismutase and catalase included in the perfusion medium significantly reduced protein excretion. Similar results were obtained with the administration of allopurinol to the rat 24h prior to kidney removal and allopurinol in the perfusion medium. [35S]Heparan sulfate loss from the glomerulus was totally inhibited by the scavenger mixture. These results suggest that reactive oxygen metabolites may be involved in damage to renal capillaries, specifically to heparan sulfate proteoglycan, which leads to proteinuria as a result of partial ischemia produced during perfusion.

Animals↗

Changes in the viscosity of hyaluronic acid after exposure to a myeloperoxidase-derived oxidant.

Both purified hyaluronic acid (HA) and bovine synovial fluid react with OCI-, the major oxidant produced by the myeloperoxidase (MPO)/H2O2/CI- system, resulting in a decrease in their specific viscosity. This reaction is inhibited in the presence of excess methionine. H2O2 alone decreases the viscosity of HA, presumably by the Fenton reaction, in the absence (but not in the presence) of the iron chelator, diethyltriaminepentacetic acid (DETAPAC). In the presence of DETAPAC, incubation of HA with the complete MPO/H2O2/CI- system lowered the viscosity of HA. Analysis of 3H-HA exposed to OCI- by gel filtration chromatography indicated that cleavage of HA occurred only at higher OCI- concentrations. We suggest that the reduction in viscosity of HA by the MPO/H2O2/CI- system may be due to a combination of oxidative cleavage and changes in the conformation of the molecule. We speculate that the changes in the molecular size of rheumatoid synovial fluid HA may be due to the action of the neutrophil MPO/H2O2/CI- system.

Chemical Phenomena↗

The pathological damage in Duchenne muscular dystrophy may be due to increased intracellular OXY-radical generation caused by the absence of dystrophin and subsequent alterations in Ca2+ metabolism.

Recent advances in the genetic and molecular pathogenesis of Duchenne muscular dystrophy and the evidence suggesting a role for oxygen free radicals (oxy-radicals) in the development of this disease are reviewed. In addition, we outline a working of hypothesis as to how disruptions in intracellular Ca2+ homeostasis within the dystrophic cell may initiate cycles of increased oxy-radical fluxes within these cells, leading to intracellular oxidative damage.

Calcium↗

The mechanism of chondrocyte hydrogen peroxide damage. Depletion of intracellular ATP due to suppression of glycolysis caused by oxidation of glyceraldehyde-3-phosphate dehydrogenase.

Exposure of articular cartilage to H2O2 in vitro inhibits proteoglycan synthesis in a fashion which parallels the inhibition which occurs in cartilage in animal models of acute inflammation. Our study shows that exposure to H2O2 also inhibits other chondrocyte functions, including total protein and DNA synthesis. Since these intracellular biosynthetic processes require adenosine triphosphate (ATP), the effect of exposure of H2O2 on chondrocyte ATP was measured. Exposure to H2O2 caused an immediate (less than 2 min) dose dependent decrease in cartilage ATP levels--found to be due to the oxidative inactivation of glyceraldehyde-3-phosphate dehydrogenase (G-3-PDH). We suggest that intrachondrocyte oxidant damage occurs through oxidation of the sensitive thiol (-SH) residue at the active center of G-3-PDH, with subsequent reduction in the rate of glycolytic ATP synthesis and the intracellular concentration of ATP which is required for DNA, protein, proteoglycan and hyaluronic acid synthesis.

Adenosine Triphosphate↗

Micromethods in single muscle fibers. 1. Determination of catalase and superoxide dismutase.

Methods have been developed for the measurements of catalase and superoxide dismutase (SOD) in single, isolated muscle fibers. These fibers are also classified according to fiber type. Catalase is determined using a fluorescent method for the measurement of hydrogen peroxide consumed. SOD measurements are carried out using a modification of established techniques whereby the inhibition of oxidation of epinephrine by SOD is assayed fluorometrically. Both enzymes may be determined in submicrogram samples of dried muscle. This approach avoids the complication of the inclusion of nonmuscle tissue with varying enzymatic activities which is frequently experienced when using homogenates of muscle, particularly diseased muscle. In addition, these techniques can be used to determine the inherent variation in SOD and catalase activities within individual fibers of the same fiber type. The Km and Vmax for catalase, determined using homogenates of human muscle, were found to be 12 mM and 1.45 mumol/min/mg dry wt, respectively. Catalase of muscle was inhibited 50% by 2 microM sodium azide. Mn-SOD contributes less than one-fifth of the total SOD activity. Therefore the activity is largely due to the Cu-Zn form of SOD. These methods are applicable to a wide variety of tissues.

Catalase↗

Micromethods in single muscle fibers. 2. Determination of glutathione reductase and glutathione peroxidase.

This paper extends the previous study for systems which control intracellular oxidative events in muscle and describes procedures suitable to assay glutathione peroxidase (GSHPx), glutathione reductase (GR), and total glutathione (GSH + GSSG) after fiber typing of individual muscle fibers. In human skeletal muscle, both GR and GSHPx activities were relatively low when compared to those of other tissue. No difference was found among fiber types (I, IIA, and IIB) with regard to GR activity, but in contrast GSHPx activity was significantly lower in type IIB fibers than in the other types. These results suggest that type IIB fibers may have a reduced ability to cope with hydroperoxides generated during oxidative stress, which, in turn, could lead to increased damage to membrane structures by lipid peroxidation or oxidation of sensitive intracellular thiol (-SH) enzymes by hydrogen peroxide. The Km of skeletal muscle GR for GSSG was 27 microM and for NADPH was 22 microM. If one assumes approximately 95% of total glutathione is present in the reduced state, then GSSG concentration would be of the order of 0.3 mmol/kg and under these conditions skeletal muscle GR would be efficient in all muscle fiber types.

Fluorescence↗

D-penicillamine reverses the inhibition of proteoglycan biosynthesis caused by exposure of cultured articular cartilage to hydrogen peroxide.

The sulphydryl containing anti-rheumatic drug D-penicillamine mildly inhibited proteoglycan synthesis in cartilage explant cultures by a mechanism not dependent upon H2O2 generation. More importantly, this drug alleviated the suppression of PG synthesis mediated by 10(-4) M H2O2 in a dose-dependent manner at concentrations of reduced drug similar to those plasma levels reported in vivo. The ability of D-penicillamine to reverse this effect was due solely to a reaction which resulted in scavenging of medium H2O2 and was not due to the "repair" of cellular lesions caused by prior exposure to H2O2.

Animals↗

Chondrocyte antioxidant defences: the roles of catalase and glutathione peroxidase in protection against H2O2 dependent inhibition of proteoglycan biosynthesis.

The production of hydrogen peroxide by polymorphonuclear cells is suspected as being a cause of cellular damage during acute inflammation. In our study, the kinetics by which hydrogen peroxide suppressed proteoglycan synthesis in cartilage explant culture suggested that the damage occurred at the level of core protein synthesis. Chondrocytes were also shown to contain both catalase and the glutathione peroxidase/reductase systems, which were both involved in the removal of 10(-4) M H2O2. Interruption of either of these peroxide metabolizing systems markedly sensitized cartilage to a greater inhibition of synthesis by H2O2. Inhibition of catalase (with 3-amino 1,2,4 triazole or azide) was found to depress synthesis further, possibly because of exposure to higher steady state levels of H2O2. Inhibition of glutathione reductase (with 1,3-bis-(choloroethyl)-1-nitrosurea) did not expose tissue to higher steady state levels of H2O2, but this treatment decreased the intrachondrocyte level of reduced glutathione which may explain the increased damage obtained in the presence of H2O2. These results support the concept that effective H2O2 metabolizing systems are important in the maintenance of normal biosynthetic rates in cartilage during inflammation.

Animals↗

The effect of pH on yields of hydroxyl radicals produced from superoxide by potential biological iron chelators.

The efficiency of conversion of superoxide to hydroxyl radicals was measured by determining the yields of fluorescent hydroxybenzoates. A variety of iron-containing catalysts were tested. Citrate was the only organic salt which showed catalytic activity at neutral pH. Adenine nucleotides had little or no activity under similar conditions. Heme proteins were inactive and any catalytic activity measured with transferrin, lactoferrin, and conalbumin could be explained by free Fe3+ released by the former two at acid pH. Many of the potential catalysts tested showed maximum activity near pH 4.8, where the rate of dismutation of O2-. is highest. This suggests that in most systems the rate-controlling step in the superoxide-driven Fenton process was the formation of H2O2. It was concluded that, with the exception of citrate, none of the biological compounds tested were able to assist the conversion of O2-. to HO. with significant efficiency at neutral pH in homogeneous solutions.

Benzoates↗