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Biomedical subjects

W H Dennis

Publications and source records attributed to W H Dennis.

At least 19 recordsLinked to original sources
PubMed1996

Testing for hepatitis B surface antigen in processing donor tissue for penetrating keratoplasty.

PURPOSE: The Food and Drug Administration recently proposed a change in the screening of eye bank cornea donors for hepatitis B virus. Currently, most eye banks run confirmatory tests to reduce the frequency of false-positive hepatitis B virus surface antigen (HBsAg) tests. The Food and Drug Administration is considering a policy that would not allow confirmatory testing. METHODS: A retrospective study of records of a regional eye bank was done to evaluate the results of screening and confirmatory tests for hepatitis B virus. RESULTS: The positive predictive value of the HBsAg screening test (using hepatitis B virus antibody neutralization for comparison) was low, 12.5%. False-positive donors accounted for 11.4% of the tissue used for penetrating keratoplasty during 1994. CONCLUSIONS: If confirmation tests were not allowed, considerable loss of suitable tissue would have occurred. We believe that the current standards allow safe and effective processing of donor ocular tissue.

Cornea↗
PubMed1987

Sensitivity of tumour cells to heat and ways of modifying the response.

In our view, the initial effect of hyperthermia on cells is the disorganization of the membrane lipid. Such disorganization alters the membrane's biophysical properties leading to passive changes in transmembrane permeability, shifts in surface charge, and altered stereoorganization of macromolecules associated with the membrane. For example, the passive permeability changes could account for the observed increase in the association of non-histone proteins to chromatin. Surface charge changes resulting from relative changes in the phospholipids could shift the concentration and types of membrane-bound proteins. Such events could initiate hyperthermic cell death. Membranes of tumour cells are characterized by elevated cholesterol. Such differences in cholesterol concentration with their attendant shift of biophysical characteristics could explain the variation in heat sensitivity between cell lines and within the cell cycle. Further support for lipids being the initial target comes from our studies demonstrating enhanced thermosensitivity when anaesthetics are present. Thermosensitivity of solid tumours is not further influenced by lidocaine in host animals fed diets enriched in linoleic acid, a diet which markedly modifies fatty acid, phospholipid patterns and cholesterol concentration of cellular membranes. One should recognize that global measures of change, such as the ratio of unsaturated to saturated fatty acids, in unsaturated fatty acid index, or percentage of unsaturated fatty acids, may not accurately reflect changes in fatty acid patterns which are related to changes in thermosensitivity. For example, we now recognize that double bond location with respect to the headgroup must be considered as well as the relative content of unsaturated fatty acids in the membrane. Further studies bearing on the role of diet and anaesthetics on cell killing and on metastatic spread are needed. An increased understanding of the relationship of membrane biophysics and biochemistry correlated with how cells respond to heat could aid in elucidating the mechanisms of cell death. Such knowledge could provide a more rational basis for cancer therapy. The association between pyrexia and tumour regression was noted as early as 1866 by Busch who observed neoplasm remission in patients afflicted with severe erysipelas (Busch, 1866). Over the past 80 years clinicians have on occasion treated tumours by heat alone or, more recently, in combination with radiotherapy (Dickson, 1979; Jensen, 1903).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Increasing the thermosensitivity of a mammary tumor (CA755) through dietary modification.

Disruption of the integrity of tumor cellular membranes has been proposed as an initiating event in hyperthermic cell death. Thermosensitivity measured by the shift in the harmonic mean of tumor regrowth delay of CA755 mammary adenocarcinomas grown in the hind legs of male BDF1, mice increased 22% when the hosts were fed a diet enriched in polyunsaturated fatty acids. Although the diet elicited the anticipated increase in tumor membrane phospholipid polyunsaturated fatty acids, the proportion of total unsaturated fatty acids decreased and the proportion of membrane-rigidifying saturated fatty acids increased. Concomitantly, the concentrations of cholesterol and phospholipid phosphorus increased and the ratio of phosphatidylethanolamine to phosphatidylcholine decreased, presumably to counter the effect of the change in the fatty acid pattern. In host liver membranes, the diet-mediated increase in proportion of polyunsaturated fatty acids was not accompanied by an increase in the proportion of rigidifying saturated fatty acids. Instead, the homeoviscous adaptation consisted of decreases in monounsaturated fatty acids and cholesterol concentration and an increase in the phosphatidylethanolamine-phosphatidylcholine ratio. Addition of a natural inhibitor of cholesterol biosynthesis to the polyunsaturated fatty acid enriched-diet reversed the diet-mediated increase in the phosphatidylethanolamine-phosphatidylcholine ratio of host liver membranes. Tumor membrane lipids from hosts fed the combined dietary factors were characterized by the formentioned rigidifying increase in saturated fatty acids and compensatory decrease in the phosphatidylethanolamine-phosphatidylcholine ratio. The inhibitor reversed the compensatory increases in cholesterol and phospholipid phosphorus concentrations. As a consequence the thermosensitivity of tumors bearing this perturbed membrane was increased.

Adenocarcinoma↗
PubMed1986

Hyperthermic sensitivity and growth stage in Escherichia coli.

Hyperthermic sensitivities of Escherichia coli B/r and Bs-1 were determined for lag-, midlog-, and stationary-phase cells at 47, 48, and 49 degrees C. In both strains midlog-phase cells were strikingly more heat sensitive (100-fold greater killing after 4 h at 48 degrees C) than stationary-phase cells, with intermediate sensitivity for lag-phase cells. In contrast to the reported difference in the radiation sensitivity between these two strains, very little difference in heat sensitivity was seen. Patterns of fatty acid composition of both strains were very similar at each phase of growth. From midlog to stationary phase, 16:1 and 18:1 unsaturated fatty acids decrease from 16 and 30% to 0.5 and 3%, respectively, while the C17 and C19 cyclopropane fatty acids increase from 7 and 3% to 22 and 25%, respectively. Concomitant with these changes in fatty acid composition, substantially higher membrane microviscosity values were recorded for stationary-phase cells. Total membrane microviscosity was positively associated with the C17 and C19 cyclopropane fatty acid composition and with cell survival following hyperthermia. In contrast to hyperthermic sensitivity, radiation survival differences between B/r and Bs-1 are little affected by growth stage. We propose that these results are consistent with a critical influence of membrane lipids on cellular hyperthermic sensitivity and further that the target sites for radiation and hyperthermia are different in these cells.

Cell Division↗
PubMed1985

A nontoxic system for 41.8 degrees C whole-body hyperthermia: results of a Phase I study using a radiant heat device.

A Phase I study of whole-body hyperthermia (WBH) (52 treatments/12 patients) was completed with no significant clinical toxicity. The study incorporated a thermal dose escalation scheme from 39.5 degrees-41.8 degrees C for up to 151 min. A radiant-heat device was utilized for producing WBH. During WBH, patients were sedated; endotracheal intubation was not required. No changes in cardiovascular, respiratory, hematological, or biochemical indices requiring clinical intervention occurred during the study. We conclude the radiant-heat device coupled with a defined pharmacological approach to WBH with appropriate patient screening yields a system for 41.8 degrees C WBH which is safe and efficient, is not labor intensive, and does not require general anesthesia and endotracheal intubation. This system is appropriate for a multimodality approach to various systemic cancers.

Adolescent↗
PubMed1984

Potentiation of differential hyperthermic sensitivity of AKR leukemia and normal bone marrow cells by lidocaine or thiopental.

Previous work has utilized spleen colony formation to evaluate the fractional survival of AKR leukemia and normal bone marrow cells after in vitro heat exposure. An inherently greater sensitivity of neoplastic cells to thermal killing, as compared to normal syngeneic stem cells, has been established both at 41.8 degrees C and 42.5 degrees C. Normal bone marrow colony-forming units were assayed in lethally irradiated (750 cGy) mice. Leukemic colony-forming units were assayed in nonirradiated mice. Using this methodology, the authors demonstrated that the differential effect of hyperthermia on AKR murine leukemia and AKR bone marrow cells can be further enhanced by the addition of lidocaine or thiopental to incubation mixtures. These findings may have application to autologous bone marrow transplantation in humans.

Animals↗
PubMed1984

Effect of whole body hyperthermia and BCNU on the development of radiation myelitis in the rat.

A radiant heat device was used to study the interaction of 41.8 degrees C whole body hyperthermia (WBH), radiation (40 Gy) and the lipophilic anti-neoplastic agent BCNU in the development of myelitis in the rat spinal cord. The addition of WBH and BCNU neither precipitated myelitis acutely nor shortened the latency before the onset of neurological signs in irradiated animals.

Animals↗
PubMed1984

A proposal for the addition of hyperthermia to treatment regimens for acute and chronic leukemia.

The application of hyperthermia to the treatment of neoplastic disease has focused on solid tumors. Human leukemias, both acute and chronic, may represent a unique category of diseases for which hyperthermia should be used in combination with other modalities with curative intent. Three clinical approaches to include hyperthermia are proposed. These are hyperthermia in combination with therapeutic low-dose whole-body irradiation, ablative high-dose total body irradiation, and bone marrow transplantation with the in vitro use of hyperthermia to purge remission bone marrow of abnormal cells. Current preclinical research further supporting these clinical applications of hyperthermia to leukemia therapy is presented.

Animals↗
PubMed1983

Lowered pH eliminates the enhanced hyperthermic killing of E. coli induced by procaine or exposure to N2 gassing.

Survival of E. coli K1060 is enhanced when they are heated at 47 degrees C in pH 6 medium as compared to pH 7.4. At pH 6 nitrogen bubbling and 10 mM procaine did not increase hyperthermic killing. The membrane content of phosphatidylethanolamine is about 80 per cent of the total of phosphatidylethanolamine, phosphatidylglycerol and cardiolipin phospholipids. The polar headgroup of this lipid is highly sensitive to pH changes in this pH range. The changes in electrostatic charge with its secondary effects on membrane-protein relationships may explain resistance to hyperthermic killing. Thus, the difference in response to lowered pH of bacterial, compared to mammalian cells may be revealing membrane-related phenomena critical to hyperthermic killing. Also increased levels of cardiolipid were observed in linolenic acid grown cells which could be an 'attempt' to stabilize their membranes.

Cell Survival↗
PubMed1983

Whole body hyperthermia with a microwave regional boost: unexpected toxicity in the pig.

An animal model was used to investigate the potential for delivering a regional temperature boost using microwave energy after whole body hyperthermia had been induced in a pig using low density, radiant heat. Thermal profiles and an unexpected toxicity in the region of the microwave energy deposition, which included the heart and liver, are reported.

Animals↗
PubMed1983

Systemic lidocaine enhancement of hyperthermia-induced tumor regression in transplantable murine tumor models.

Previously, we reported that local lidocaine infusion of a CA 755 mammary adenocarcinoma growing in C57BL X DBA/2 F1 mice, when combined with local heating for 1 hr in a 43.5 degrees water bath, significantly increased survival and inhibited tumor growth more than heating alone. Because of its clinical implications, systemic lidocaine was tested in the above model system and in a murine fibrosarcoma tumor model. An equivalent supraadditive, tumor-inhibitory effect of heat and lidocaine was obtained with both systemically and intratumor-administered lidocaine. The serum levels of lidocaine necessary to achieve tumor regression were within the therapeutic range for the control of arrhythmia in humans. Several treatment schedules, varying the mode of drug delivery, were evaluated. The effects of treatment on tumor growth characteristics were analyzed using an extension of the Cox survival model.

Animals↗
PubMed1983

Differential sensitivity of AKR murine leukemia and normal bone marrow cells to hyperthermia.

To determine if there is a differential effect of hyperthermia on AKR murine leukemia and AKR normal bone marrow cells incubated in vitro, the fractional survival of leukemic and of normal cells with proliferative potential as a function of heating exposure was estimated by evaluating spleen colony formation. Normal bone marrow colony-forming units were assayed in lethally irradiated (750 centigrays) mice; leukemic colony-forming units were assayed in nonirradiated mice. Electron micrographic studies of leukemic cells treated with 41.8 degrees hyperthermia found that structural damage to the cell, i.e., changes in the Golgi apparatus, was associated with the lack of ability to form colonies. AKR leukemia cells were more sensitive than normal cells to hyperthermic killing at 41.8 degrees and at 42.5 degrees. This differential was found whether cells of each type were heated separately or when mixed together. This model system demonstrates an inherently greater sensitivity of neoplastic cells, as compared to normal syngeneic stem cells, to thermal killing. This finding may have relevance to autologous bone marrow transplantation in humans.

Animals↗
PubMed1982

Correlation of bacterial hyperthermic survival with anaesthetic potency.

We have evaluated several local anaesthetics and hypnotics for their relative ability to influence hyperthermic cell killing. Bacterial cell survival following exposure to heat and anaesthetic was used as the assay system. The E. coli bacterium used was the unsaturated fatty acid auxotroph, K1060. It was grown at 37 degrees C in medium supplemented with oleic acid and then exposed to 47 degrees C hyperthermia in the presence of an anaesthetic. The local anaesthetics tested were procaine, lidocaine, tetracaine, and benzocaine, and the general anaesthetics were barbital and pentobarbital. The dose response for each anaesthetic was determined over a five-hour heating period. The anaesthetic concentration required during heating to halve the time for cell killing found with heat alone is 5.9 mM for procaine, 0.8 mM for lidocaine, 0.12 mM for tetracaine, 2.0 mM for benzocaine, 6.7 mM for barbital and 1.2 mM for pentobarbital. There is a direct correlation between equivalent effect doses of the local anaesthetics and published data for the relative potency of the same anaesthetics as determined by respiratory arrest in mice and by myocardial contractile force in dogs. The assay we have described would be a convenient and easy test for the interaction of these drugs with hyperthermia. The use of this interaction with hyperthermia as an adjuvant in combined radiation-hyperthermia therapy should be tested.

Anesthetics, Local↗
PubMed1981

Correlation of hyperthermic sensitivity and membrane microviscosity in E. coli K1060.

We have demonstrated a positive correlation between membrane microviscosity and the temperature required to kill E. coli. Batches of cells with differing unsaturated fatty acid (u.f.a.) compositions were prepared from the u.f.a.-requiring E. coli K12 mutant K1060. The membrane microviscosity of these cells is estimated from the extent of fluorescence polarization of the probe molecule 1,6-diphenyl-1,3-5,-hexatriene dissolved in the membrane. For the same growth temperature, cells grown in oleic acid (18:1) have a greater microviscosity and u.f.a. content than linolenic acid (18:3) grown cells. the rate of decrease in microviscosity with increasing temperature is correlated with the amount of u.f.a. present in the membrane. From survival curves determined at several hyperthermic exposures, one can interpolate the hyperthermic temperature required to kill 90 per cent of the cells in three hours. These equivalent kill temperatures are directly related to the cell microviscosity. These data support the hypothesis that cell membrane microviscosity plays a critical role in hyperthermic killing.

Escherichia coli↗
PubMed1980

Acid hydrolysis of military standard formulations of diazinon.

Acid hydrolysis is a means of disposal of diazinon, O,O-diethyl-O-(2-isopropyl-4-methyl-6-pyrimidinyl)-phosphorothioate. Procedures were developed for the hydrolysis of three military standard diazinon formulations (47.5% emulsifiable concentrate, 2% dust and 0.5% oil solution). The kinetics of hydrolysis at four temperatures were obtained for each formulation in order to predict the half-life of diazinon between 5 degrees and 50 degrees C. The toxicities of the reaction mixtures were evaluated by aquatic bioassay with bluegill sunfish (Lepomis macrochirus). When the hydrolysis of a formulation had reduced the diazinon concentration by greater than 99.9%, there was less than 50% reduction in the toxicity of the reaction mixture to bluegill sunfish. Analysis of reaction mixtures showed that the toxic component was O,O,O,O-tetraethyldithiopyrophosphate (Sulfotepp), which was present in all diazinon formulations.

Animals↗