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Biomedical subjects

J W Harris

Publications and source records attributed to J W Harris.

At least 73 records · Page 4Linked to original sources
PubMed1986

Evaluation of a new triphasic oral contraceptive in private practice.

We evaluated the clinical and metabolic effects of a new triphasic regimen developed in the continuing attempt to reduce the dose of estrogen and progestogen in oral contraceptives. A combination of ethinyl estradiol (EE) and levonorgestrel (LNg) was used (six tablets with 30 micrograms EE + 50 micrograms LNg, five tablets with 40 micrograms EE + 75 micrograms LNg, and 10 tablets with 30 micrograms EE + 125 micrograms LNg), also known as Triphasil (Wyeth). In a private practice, 409 subjects participated in 7,286 treatment cycles. Three pregnancies occurred, all due to subject failure. Menstrual regulation was excellent and the incidence of side effects extremely low. Withdrawals from the study for possibly drug-related medical reasons totaled 9.0% through 56 cycles of treatment. Metabolic changes also were evaluated in 14 of these women over a 6-month period. The only statistically significant increase in carbohydrate values occurred at 6 months. The mean glucose level at 30 minutes of the oral glucose tolerance test was above the baseline mean value, but serum insulin levels showed no statistically significant deviation. Lipid values presented are total lipids, total cholesterol, triglycerides, alpha-, beta-, and pre-beta-lipoproteins, and high density and low density lipoprotein cholesterol. There was no statistically significant difference between the mean values at baseline and those during treatment for any lipid variable. These results indicate that this triphasic oral contraceptive has a high degree of efficacy, a low incidence of side effects, excellent cycle control, and high subject compliance, and would seem to indicate a minimal influence on the metabolism of lipids and carbohydrates in the small number of subjects studied.

Blood Glucose↗
PubMed1986

Effects of glutathione depletion by buthionine sulfoximine on the sensitivity of EMT6/SF cells to chemotherapy agents or X radiation.

The effects of depletion of cellular glutathione (GSH) on the sensitivity of cultured EMT6/SF cells to chemotherapy agents or x rays under hypoxic and aerated conditions were investigated. Buthionine sulfoximine (BSO), a potent inhibitor of the enzyme gamma-glutamyl-cysteine synthetase, was used to deplete cellular GSH. Addition of BSO (50 microM) to EMT6/SF cultures depleted cellular GSH with a half-time of approximately 2 hr. Cellular GSH reached very low levels within hours of addition of BSO. After removal of BSO, cellular GSH recovered with approximately the same kinetics as was seen for depletion. Incubation of EMT6/SF cells with BSO concentrations of up to 1 mM did not reduce the viability or inhibit growth when exposure was limited to times less than 24 hr. However, for longer exposure times, toxicity and growth inhibition were demonstrated in a dose dependent fashion. EMT6/SF cells were treated with chemotherapy agents under either aerated or extremely hypoxic conditions. Cells were more sensitive to cis-dichlorodiammino Pt(II) (DDP), mitomycin C (MitC), L-phenylalanine mustard (L-PAM), and nitrogen mustard (HN2) when treatment was under hypoxic conditions. The magnitude of this sensitization under hypoxic conditions ranged from a dose modifying factor (DMF) of 1.4 (HN2) to 4.1 (MitC), measured at the 0.1 level of cell survival. Hypoxic EMT6/SF cells were more resistant to the cytotoxic effects of actinomycin D (ActD) under hypoxic conditions (DMF = 10 at SF = 0.3). When cellular GSH was depleted to less than 5% of control by treatment with 50 microM BSO for 12-14 hr, cells were sensitized to DDP, L-PAM and HN2 under both aerated and hypoxic conditions. DMF's ranged from 1.4-6.5, depending on the agent. Hypoxic cell sensitization was never significantly greater than that seen in aerated cells, as was the case for X radiation (DMF = 1.3 for hypoxic cells only). GSH depletion also sensitized to MitC, but only under aerated conditions (DMF = 2.1). Hypoxic EMT6/SF cells were not sensitized to MitC by depletion of GSH. GSH depletion afforded slight protection against ActD toxicity under both aerated and hypoxic conditions. These studies suggest that cellular GSH plays an important role in modifying cellular response to cytotoxic drugs. GSH depletion may sensitize tumor cells to some chemotherapy agents, but differential sensitization of tumors compared to normal tissues, based on hypoxic tumor cells as targets, would not be expected based on these in vitro experiments.

Animals↗
PubMed1986

Cellular glutathione, thermal sensitivity, and thermotolerance in Chinese hamster fibroblasts and their heat-resistant variants.

HA-1 Chinese hamster fibroblasts and two heat-resistant variants, designated 2242 and 3012. have been investigated to determine the role that glutathione (GSH) plays in intrinsic cellular resistance to heat and in the development of thermotolerance. The constitutive levels of GSH did not correlate with intrinsic heat sensitivities, but depletion of GSH sensitized all three cell lines to thermal stress. After heating (43.5 degrees C/2 h), surviving fractions were 1 X 10(-3), 1 X 10(-2), and 8 X 10(-3) for HA-1, 2242, and 3012 cells, respectively. Depletion of cellular GSH with L-buthionine-S, R-sulfoximine to less than 10% of control values sensitized such that the thermal responses of these three cell lines were nearly indistinguishable at 43.5 degrees C. Surviving fractions were 2 X 10(-4), 1 X 10(-4), and 1 X 10(-4) for L-buthionine-S,R-sulfoximine-treated HA-1, 2242, and 3012 cells, respectively, following heating at 43.5 degrees C for 2 h. The development of thermotolerance in HA-1 cells following heat shock (45 degrees C/15 min) was unaffected by the inhibition of GSH synthesis. On the other hand, when GSH levels were maintained at extremely low levels, the development of thermotolerance was inhibited. In addition, following heat shock, cellular GSH was decreased and remained below control levels during the development of thermotolerance.

Animals↗
PubMed1986

Oxygen saturation with sleep in patients with sickle cell disease.

Ear oximetry was used to monitor arterial oxygenation in seven patients who had a history of frequent admissions for sickle cell crisis and were taking narcotic analgesics. Five full-night studies and seven daytime "nap" studies were performed in which sleep state was monitored by electroencephalography, and respiratory rate and tidal volume were monitored by inductance plethysmography. For all patients the mean (+/- SEM) of the median oxygenation values was 93.3% +/- 0.4% during wakefulness and 91.4% +/- 0.8% during sleep. During wakefulness the lowest saturation was 90% +/- 0.5%; during sleep there was a fall in the lowest oxygen saturation to 86.5% +/- 0.9%. In all patients a fall in oxygen saturation was associated with a decrease in respiratory depth without a change in respiratory frequency. The results indicate that in sickle cell disease oxygen saturation is lower during sleep than during wakefulness and that hypoxemia can be attributed to a fall in tidal volume.

Adult↗
PubMed1985

The in vitro sensitivity of chronically hypoxic EMT6/SF cells to X-radiation and hypoxic cell radiosensitizers.

We have investigated the effect of extreme, prolonged hypoxia on the radiosensitivity of EMT6/SF cells in vitro. As cells were kept hypoxic for 1-24 h, their radiosensitivity increased, but no further change was noted for hypoxic incubation beyond 24 h. Chronically hypoxic (45 h) cells were more radiosensitive than acutely hypoxic (1 h) cells by a factor of 1.43. When chronically hypoxic cells were re-aerated, the increased radiosensitivity persisted, although it was reduced. Misonidazole (MISO) radiosensitization was equally effective under conditions of acute and chronic hypoxia. In contrast, MISO, SR2555 and SR2508 were more cytotoxic in chronically hypoxic cultures than in acutely hypoxic cells. Measurements suggested that intracellular thiols may play an important role in the effects observed.

Animals↗
PubMed1985

Neuromuscular blockade in dystrophia myotonica with atracurium besylate.

The anaesthetic management of a young woman with dystrophia myotonica is described. The use of atracurium and monitoring of neuromuscular block allowed suxamethonium and neostigmine to be avoided, and thereby to reduce the risk of myotonic contractions. No adverse sequelae were observed.

Adult↗
PubMed1985

Some properties of hemoglobin mobile (alpha 2 beta 2 73 Asp----Val).

A hemoglobin variant was identified as hemoglobin Mobile in which valine replaces the normal aspartic acid at beta 73. Studies of its oxygen equilibria and of its interactions in gelation when mixed with hemoglobin S were carried out. Hemoglobin Mobile had an oxygen affinity lower than that of hemoglobin A, as observed by others. However, in mixtures with hemoglobin S, hemoglobin Mobile appeared to impair gelation or increase solubility to a slightly greater extent than did hemoglobin A. Beta 73 is a known site of intermolecular interactions in polymers of hemoglobin S. Our studies suggest that the impairment of hemoglobin S polymer formation by altered intermolecular interactions is significantly less in Hb Mobile than in Hb Korle-Bu in which beta 73 is asparagine.

Blood Protein Electrophoresis↗
PubMed1985

Diphenylhydantoin-induced pure red cell aplasia.

The pathogenesis of diphenylhydantoin-induced pure red cell aplasia was investigated in the case of a 32-year-old man who developed pure red cell aplasia while he was under treatment with diphenylhydantoin. The patient's serum IgG purified from serum drawn at the time of diagnosis suppressed normal allogeneic marrow colony-forming (CFU-E) and burst-forming (BFU-E) and autologous blood BFU-E growth in vitro only in the presence of diphenylhydantoin. This IgG-diphenylhydantoin complex had no effect on CFU-GM growth in vitro. Normal IgG or patient's IgG purified from serum drawn after the remission of red cell aplasia had no effect on erythroid colony formation in vitro in the presence of diphenylhydantoin. The IgG-diphenylhydantoin complex exerted no direct cytotoxic effect on normal marrow erythroblasts, CFU-E, and BFU-E, nor did it interfere with the action of erythropoietin on marrow erythroblasts. These studies suggest that diphenylhydantoin-induced red cell aplasia is immunologically mediated through an IgG inhibitor, which requires the presence of the drug to suppress erythroid colony formation in vitro. This inhibitor seems to exert its effect on erythroid progenitors at or beyond the stage of differentiation of CFU-E, but not on erythroblasts.

Adult↗
PubMed1984

Growth of chlamydia in pig lung alveolar macrophages; preparation of macrophages and demonstration of growth.

The harvesting, storing and utilisation in tissue culture of lung alveolar macrophages from 2-3 weeks old piglets were investigated. An average yield of 4 X 10(8) cells was obtained, which in culture usually remained healthy for at least 8 days. In liquid nitrogen at -173 degrees C about 50% of the cells were still viable after 3 months. Pig cells sustained the growth of ovine Chlamydia psittaci and a rising titre was demonstrated over 4 passages.

Animals↗
PubMed1984

Experimental chlamydial pneumonia in pigs.

Naturally occurring disease in pigs associated with chlamydial infections has not been reported in Britain, though evidence of chlamydial challenge has been demonstrated in two separate serological surveys. An isolate of Chlamydia psittaci (28/68) from an ovine pneumonia produced pneumonia in pigs following intratracheal inoculation. Transient pyrexia at 24 hr was followed by increased respiratory rates and inappetance which lasted for a further 48 hr in challenged pigs. Histologically acute exudative reactions were present in the lungs by 24 hr with proliferative changes predominating after 10 days. While variations in the concentrations of inocula were reflected by corresponding increases and/or decreases in gross lung damage, clinical signs and histological reactions were unaltered. Chlamydial organisms were recovered only from lung tissues.

Animals↗
PubMed1984

Initial report of the phase I trial of the hypoxic cell radiosensitizer SR-2508.

From March 15, through August 31, 1983, 37 patients have been entered on the RTOG Phase I trial of SR-2508. The drug was given intravenously three times weekly for three weeks. The starting total dose was 11.7 g/m2 and the highest total dose given was 32 g/m2. The lower lipophilicity of SR-2508 has produced the expected decrease in terminal half-life (5.4 hrs) of drug excretion and increase in total drug excreted unchanged in the urine (71%) compared to misonidazole or desmethylmisonidazole. The maximum single dose (3.7 g/m2) administered was well tolerated. With multiple doses peripheral neuropathy is the dose-limiting toxicity. The lowest cumulative dose producing toxicity was 21.6 g/m2, the highest non-toxic dose was 29.7 g/m2. The use of an individual patient's drug exposure as measured by the area under the curve of drug concentration vs time may be an excellent predictor of toxicity. This may eventually permit individualization of dose and prevention of serious toxicity. A single dose of 2 g/m2 will produce a tumor concentration of drug (approx. 100 micrograms/ml) that will yield a sensitizer enhancement ratio of 1.5 to 1.7. Using a starting dose of 2 g/m2 three times weekly, patients are now being studied on a five week drug schedule to further evaluate predictability of drug toxicity in preparation for clinical trials of drug efficacy.

Drug Evaluation↗
PubMed1983

Non-volatile fatty acids in the diagnosis of non-specific vaginitis.

In the vaginal washings of 100 women with symptomatic non-specific vaginitis a succinate/lactate ratio of greater than or equal to 0.4 had a diagnostic sensitivity of 80%, a specificity of 83% for this condition. The predictive value of a positive test was 94%, but that of a negative test was only 55%. A strong association between the presence of Gardnerella vaginalis, anaerobes, a vaginal pH of above 4.5, and amines was found not only in non-specific vaginitis, but also in trichomonal and gonococcal infection. A variety of primary changes may encourage the multiplication of both gardnerellae and anaerobes and their presence in non-specific vaginitis may be a secondary rather than a primary event.

Female↗
PubMed1983

Viscosity studies of deoxyhemoglobin S: evidence for formation of microaggregates during the lag phase.

To look for evidence for the formation of deoxy S microaggregates during the lag phase, the kinetics of gelation of purified deoxy S in dilute phosphate buffer were continuously monitored by a Wells-Brookfield cone and plate microviscometer. Three separate manipulations were performed during the lag phase. (1) The rotating cone of the viscometer was stopped for varying intervals and then restarted. (2) Samples were withdrawn from runs in mid-to-late lag phase ("poised") and reintroduced early in the lag phases of other runs with appropriate volume, temperature, and concentration adjustments. (3) Deoxy S was partially replaced in mid-lag phase by solutions with equivalent volumes, temperatures, and concentrations of deoxy A, F, or C or deoxygenated albumin. The results support the conclusions that (1) irreversible microaggregates are formed early in the lag phase, (2) their formation is favored by stirring, and (3) they are stable if the shearing is stopped for intervals up to six times the total lag times of control runs. Replacement of deoxy S by an equivalent concentration of deoxygenated nonsickle protein during the lag phase does not change the lag time, whereas mixtures of sickle hemoglobin and other proteins made before the reaction is initiated by temperature jump have markedly prolonged lag times. This suggests that once microaggregates of deoxy S are formed, the excluded volume effect of deoxygenated nonsickle hemoglobins or albumin supports polymerization at the same rate as sickle hemoglobin. These results are consistent with the proposed equilibrium nucleation/irreversible growth model of nucleation.

Albumins↗
PubMed1983

Effects of extreme hypoxia on the growth and viability of EMT6/SF mouse tumor cells in vitro.

The purpose of this study was to characterize a model system in which to study hypoxic cell biology in vitro as a function of time under extremely hypoxic conditions. EMT6/SF cells that were maintained at 37 degrees under hypoxic conditions showed no increase in cell number for up to 70 hr. The mitotic index of hypoxic cultures was less than 0.1%, compared to 2.3 to 3.0% in aerated cultures. The plating efficiency of hypoxic cells decreased with time to 20 to 30% of control values by 70 hr. Aerated cultures consumed glucose more rapidly than did hypoxic ones, due to increasing cell number in air. But, on a per cell basis, hypoxic and aerated cells consumed glucose at equal rates (congruent to 1.2 X 10(-4) micrograms/cell/hr). Virtually 100% of the glucose consumed was converted into lactic acid in both aerated and hypoxic cultures. The labeling index and rate of incorporation of [3H]thymidine decreased exponentially with time in hypoxia. However, the percentage of cells with S-phase DNA content remained nearly constant for up to 72 hr. The rate of protein synthesis was suppressed in hypoxic cultures to between 20 and 50% of control (aerated) rates. When cultures were reaerated following 45 hr of hypoxia, congruent to 12 hr was required for resumption of DNA synthesis and cell division. The application of this system to further study of hypoxic cell biology is discussed.

Animals↗
PubMed1982

Magnetic-susceptibility measurement of human iron stores.

We made direct noninvasive magnetic measurements of hepatic iron stores with a specially designed superconducting quantum-interference-device (SQUID) susceptometer in 20 normal subjects and in 110 patients with liver disease, iron deficiency, hereditary hemochromatosis, or transfusional iron overload. Magnetic in vivo measurements of liver non-heme iron were closely correlated with chemical in vitro measurements in liver-biopsy specimens (r = 0.98, P less than 10(-5) up to 115 mumol per gram of liver tissue (wet weight) or more. Magnetically determined storage-iron concentrations were below 6.0 mumol per gram in iron-deficient patients and normal men and premenopausal women, but they were raised (9.7 to 31.4 mumol) in 12 of 67 patients with liver disease and were greatly increased (22.9 to 117.7 mumol) in patients with untreated hereditary hemochromatosis or transfusional iron overload. Magnetic measurements of iron stores provide a new quantitative technique for early detection of hereditary hemochromatosis and for rapid evaluation of treatment regimens for transfusional iron overload.

Female↗