Biomedical subjects
Publications and source records attributed to J M Bowen.
Metoclopramide, a dopamine-2 agent, has been shown to be useful in the antagonism of fescue toxicosis in grazing steers. The determination of this drug is described for the purpose of pharmacokinetic study and consideration of potential delivery devices to combat this economically significant condition.
Following acute accidental death of 26 cows exposed to boron fertilizer, effects of inorganic boron treatment in goats were studied. Goats were orally dosed with toxic but sublethal amounts of the fertilizer. Multiple hematologic and serum chemistry parameters were assessed, as were cerebrospinal fluid (CSF) neurotransmitters and some of their metabolites. Significant increases in packed cell volume, hemoglobin, inorganic phosphate, creatine phosphokinase, conjugated bilirubin, sodium, glucose, cholesterol, and aspartate transaminase were recorded. The following serum components were significantly decreased after boron dosing: alkaline phosphatase, magnesium, glutamyltransferase and potassium. There was evidence of a stimulatory effect on both serotonergic and dopaminergic neurons as reflected in elevated CSF monoamine metabolites. Aberrations in clinical behavior, including seizure-like activity, also suggested a central nervous system effect of inorganic boron.
A computer spreadsheet was developed to predict the economic impact of a management decision to use B-mode ultrasonographic ovine pregnancy diagnosis. The spreadsheet design and spreadsheet cell formulas are provided. The program used the partial farm budget technique to calculate net return (NR) or cash flow changes that resulted from the decision to use ultrasonography. Using the program, either simple pregnancy diagnosis or pregnancy diagnosis with the ability to determine singleton or multiple pregnancies may be compared with no flock ultrasonographic pregnancy diagnosis. A wide range of user-selected regional variables are used to calculate the cash flow changes associated with the ultrasonography decisions. A variable may be altered through a range of values to conduct a sensitivity analysis of predicted NR. Example sensitivity analyses are included for flock conception rate, veterinary ultrasound fee, and the price of corn. Variables that influence the number of cull animals and the cost of ultrasonography have the greatest impact on predicted NR. Because the determination of singleton or multiple pregnancies is more time consuming, its economic practicality in comparison with simple pregnancy diagnosis is questionable. The value of feed saved by identifying and separately feeding ewes with singleton pregnancies is not offset by the increased ultrasonography cost.
The effects of an organophosphate (OP) pesticide, fenthion (FEN), on the release and metabolism of dopamine were evaluated in a clonal line of rat pheochromocytoma (PC12) cells. HPLC was used to determine media concentrations of DA and the DA metabolites norepinephrine (NE), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). The FEN formulation solvent did not significantly affect DA metabolism. In the first study, cultures were treated with 10(-5) or 10(-6) M FEN or 10(-5) M neostigmine, a non-OP acetylcholinesterase inhibitor. Concentrations of both catecholamines were elevated in cultures treated with 10(-5) M FEN by 2.8-fold for DA and 3.5-fold for NE. Neostigmine effects were of smaller magnitude and DA was decreased after 24 hr. Cultures were also treated with depolarizing levels of K+, but the effect of FEN was not altered, suggesting that FEN does not act by increasing DA release. In the second study, the effect of 10(-6) M FEN was evaluated in cultures treated with the DA uptake inhibitor benztropine, the monoamine oxidase (MAO) inhibitor pargyline, or the catechol-O-methyltransferase (COMT) inhibitor tropolone. Inhibitor effects were consistent with their known mechanisms of action. In all cultures treated with FEN, the ratio HVA/DOPAC was decreased after 3 and 6 hr of exposure. A decrease in HVA/DOPAC was also observed in cultures treated with neostigmine and tropolone. In combination with pargyline, FEN decreased DA in contrast to its usual effect of increasing DA. Neither the stimulation of DA release nor the inhibition of DA uptake affected the observed action of FEN in PC12 cultures.(ABSTRACT TRUNCATED AT 250 WORDS)
Organophosphates (OP) comprise one of the major classes of pesticides in use today. It is well accepted that the primary site of action of the OPs is at cholinergic synapses. However, it has been suggested that OPs may have direct neural effects as well. In this study, cultured chick dorsal root ganglia (DRG) were used to study the effect of fenthion (FEN), an OP pesticide, on isolated nerve cell growth and ultrastructure. Light microscopic evaluation revealed a dose-response relationship between the concentration of FEN (10(-2) M to 10(-5) M) and severity of morphologic changes. Cultured explants were treated with a lower concentration of FEN (10(-6) M) and morphologic alterations were compared to those observed in explants treated with 10(-6) M paraoxon, a more acutely toxic OP, or 10(-6) M neostigmine, a non-OP inhibitor of acetyl-cholinesterase. Based on both light and electron microscopy, neostigmine had no observed effect on cell morphology except for an inhibition of the extension of neurites by DRG cells. In contrast, explants treated with OPs exhibited a significant alteration in cell morphology. Initial lesions were observed first in the neurites and pseudopodia and consisted of vacuolization, loss of tubular structures, retraction of pseudopodia, and cell membrane disruption at the growth cone. Lipid accumulations were observed within the cytoplasm of treated cells. The effects of paraoxon on DRG cell morphology were significantly more severe than the effects of FEN, and lipid vacuoles observed in paraoxon-treated cells were several times larger than those observed in FEN-treated cells (5-10 microns in diameter vs. 0.5-1.0 microns in diameter). Results show that OPs have a direct effect on DRG nerve cells in culture, consistent with an alteration in cell membrane integrity. Cultured DRG cells can be useful in the evaluation of toxicologic effects.
A randomized, controlled study was performed in patients with high-risk, untreated squamous cell carcinoma of the uterine cervix to evaluate the adjunctive use of viral oncolysate (VO) prepared from the SW756 cell line. Seventy-five patients were stratified by tumor volume and randomized to receive radiation therapy (RT) alone or RT plus intradermal immunization with VO. Fifty-one (68%) patients relapsed with a median survival (MS) of 29.1 months and a median progression-free interval (MPFI) of 18.0 months. No differences in MS or median PFI were observed by treatment arm or site of relapse, although a trend toward improved MS and median PFI in patients with small-volume primary lesions was suggested. Serum surface-binding antibody activity (greater than or equal to 1:8) to the SW756 cell line was detected in 14 of 41 unselected patients prior to therapy. Virus hemagglutination inhibitory activity (greater than or equal to 1:8) was detected in 37 of 41 patients before treatment. four-fold increases in titer were observed to the SW756 cell line in 83% and to influenza in 74% of patients tested after immunization. Preirradiation measurements of phytohemagglutinin-induced blastogenesis by the relative proliferation index (RPI) method in 39 patients revealed RPI values less than 0.58 in nine patients, eight of whom relapsed. At 3-6 months after the initiation of irradiation, 32 of 39 patients had values less than 0.58. Patients in the RT group with values less than 0.58 had significantly more relapses than those who received RT plus VO.
Electroacupuncture was used to treat lameness in horses and ponies with chronic laminitis (n = 10) or navicular disease (n = 10). A clinical trial was conducted with random allocation of equal numbers of animals to control and treatment groups. Acupuncture was performed three times per week for four consecutive weeks. The degree of lameness was assessed by 1) a grading scheme, 2) measurement of stride lengths and 3) analysis of weight distribution using a force plate. Although seven out of ten animals with chronic laminitis improved clinically during the trial, there were no statistically significant differences between treatment and control groups. Six out of ten horses with navicular disease improved, but there were no significant differences between treatment and control groups.
Six patient with malignant effusions (five with ascites and one with malignant pleural effusion) due to refractory ovarian carcinomatosis, received intracavitary injections of ovarian viral oncolysate (VO). Measurements were made of the intracavitary activities of T cell growth factor (TCGF-IL-2) and B cell growth factor 12-kD (BCGF) and these were correlated with the clinical activity and cytologic changes in the malignant effusions. Both BCGF and IL-2 activities were demonstrated in malignant effusions prior to therapy although these were relatively higher for BCGF. Increases in the activities of both lymphokines were observed in the post VO treatment samples ranging from 4.1% to 45.0% for BCGF and 4.8% - 33.9% for IL-2. One patient who exhibited marked clinical improvement accompanied by mononuclear cell infiltrates and diminution of ascitic fluid malignant cells, also had elevation of lymphokine activities after repeated VO injections. These data provide further support for the role of VO as inducers of regional immunity.
Viral oncolysates (VO) derived from two cultured ovarian carcinoma cell lines infected with influenza A/PR8/34 were administered intraperitoneally (IP) to 40 patients with advanced ovarian carcinoma, including 31 with late-onset ascites and 5 with pleural effusions. PR8 virus-specific antigens and ovarian tumor-associated antigens have been demonstrated on two oncolysates designated OVO1 and OVO2. Thirty-five patients received 9 mg of a 1:1 mixture of OVO1 and OVO2, 5 patients received one or the other. During the first month three IP schedules were evaluated, i.e., single, biweekly, and weekly, which were followed by monthly injections. Intrapleural (IP1) injections of a 3.0-mg 1:1 mixture of OV1 and OV2 were administered to 3 patients concurrently with initial IP injections and to 2 patients following later development of pleural effusions. In 7 patients ascites disappeared; in 5 of these the number of cytologically detected malignant cells was markedly reduced, in 1 pleural effusion disappeared, and in 3 tumor masses were reduced. Tumor masses shrank also in 2 patients without ascites. Tumor reduction conformed to standard response criteria in 2 of the 5 patients. Response duration in the 9 responding patients lasted from 3 to 19 months and survival durations 4 to 42 months. Disease symptoms in 7 patients improved noticeably. Two of the 9 responders later developed unilateral pleural effusions that responded for 7 and 15+ months to a single IP1 injection. Seventeen patients experienced one or more treatment side effects including fever, nausea or anorexia, malaise, abdominal pain, and arthralgia, but in only 2 patients, both on the weekly schedule, was toxicity severe enough to require treatment withdrawal. Humoral responses to viral and tumor cell-surface antigens were frequently observed in patients demonstrating clinical activity.
Chronic exposure to organophosphates (OP) can result in nonspecific neurologic signs in both man and animals. Improved methods are needed to predict toxicity and to better characterize neuromuscular effects. In this study, dogs were exposed to an OP (fenthion) by weekly dermal application of a 20% solution at a dosage of 44 mg/kg. This dosage does not produce signs of acute OP toxicity in dogs, although plasma cholinesterase (ChE) levels are significantly decreased. Electromyograms (EMG) were used to monitor motor unit potential (MUP) activity at minimal and submaximal contractile effort in four different muscles. At 1-month intervals, muscle biopsies were obtained and plasma ChE levels were determined. At 3 months, hyperreflexia and/or mild proprioceptive deficits were observed. The dosage was reduced to 22 mg/kg for the remaining 3 months of the study. At the end of this 6-month study, nerve and muscle biopsies were obtained. Mean plasma ChE levels were decreased (preexposure value of 1775 IU/liter to low of 310 IU/liter) and correlated with duration of exposure and change in dosage level. Fourier analysis of EMG indicated some increase in higher frequency components of the power spectrum with time, and analysis of individual MUPs revealed a significant (p less than 0.05) increase in the product of the amplitude times the duration of the potentials in all muscles examined. Biopsy results were supportive of EMG findings of altered neuromuscular function and loss of small motor units. The EMG changes were most consistent in the gastrocnemius muscle and were detected prior to development of clinical signs. These results indicate that EMG can be useful in monitoring OP exposure and predicting toxicity.
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In this report, data are presented to show that transformation-associated proteins (TAP) secreted from the transformed 6M2 cells have mitogenic activities in the stimulation of DNA synthesis and proliferation of normal rat kidney (NRK-2) cells and of nonpermissively grown 6M2 cells. TAP also bound specifically to NRK-2 cells with a binding dissociation constant (Kd) of 1.4 pM. Approximately 2 X 10(5) binding sites per cell were found. Therefore, TAP may represent a set of virally-induced growth stimulatory factors.
The 6M2 cell line was established by transformation of normal rat kidney cells with the ts110 mutant of Moloney murine sarcoma virus (Mo-MSV). P85gag-mos was found to be the only known viral-transforming protein in this cell system. Previously, we described the detection in 6M2 cells of rat-specific transformation-associated proteins (TAPs) using a monoclonal antibody (MC). In this study, we used MC to investigate further the expression of TAPs at different temperatures and the time course of turn-on and shut-off of TAPs upon temperature shifting. It was found that TAPs were expressed at 24, 28 and 33 degrees C, but not at 37 and 39 degrees C. In experiments of temperature shifting, TAPs reappeared in about 6 h in 6M2 cells after the temperature was shifted from 39 to 33 degrees C, following closely the reappearance of P85gag-mos. The data in this communication support the notion that TAPs might be activated by the v-mos gene product during the process of transformation.
We have produced a monoclonal antibody (MAb), designated 11G12, of IgG1 isotype that recognizes group-specific epitopes of the HBsAg. It was demonstrated that the same MAb 11G can be used effectively as both the capture and tracer antibody to detect HBsAg in human plasma samples, using sandwich radioimmune assays (11G-11G sRIA) and sandwich avidin-biotin types of enzymatic assays (11G-11G sABC). The sensitivities for 11G-11G sRIA and 11G-11G sABC is 2.5 ng/ml and 5.0 ng/ml of HBsAg, respectively. Our data suggest that sufficient numbers of the same epitope exist on the HBsAg so that the use of the same MAb as both capture and tracer antibody does not reduce the sensitivity of the assays. The use of MAb 11G as both capture and tracer also minimizes the "hook effect" often encountered in testing high concentrations of plasma HBsAg by other assays. We also experimented with a sandwich RIA in which MAb 11G was used as the capture and polyclonal anti-HBs antibody as the tracer and found that such a combination increased the sensitivity of detection to 1.25 ng/ml of HBsAg.
Naturally occurring or iatrogenic hyperadrenocorticism was associated with myopathy in six dogs. One dog had muscle weakness and muscle atrophy but normal electromyographic findings. Five dogs had muscle stiffness, proximal appendicular muscle enlargement, and myotonic discharges on electromyography. Histologic, electron microscopic, and histochemical findings in the musculature of dogs that were examined were characteristic of noninflammatory degenerative myopathy. Clinical signs of the myopathy improved to varying degrees in five dogs that were treated for the hyperadrenocorticism.
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Mouse mammary tumor virus (MMTV) derived from the culture medium of GR cells contained seven proteins, identified as gp55, gp33, p25, pp20, p16, p12, and p10. The major viral phosphoprotein was the 20,000-molecular-weight protein, pp20. Immunoprecipitation of cytoplasmic extracts from pulse-labeled GR cells identified three MMTV gag-specific proteins, termed Pr78(gag), Pr110(gag), and Pr180(gag+). These intracellular polyproteins were precipitable from cytoplasmic extracts by antisera to virions p25 and p12 but not by antisera to gp55. The major intracellular gag-specific precursor polyprotein, Pr78(gag), contained antigenic determinants and tryptic peptides characteristic of p25, p12, p10, and presumably pp20. This precursor is presumably derived from nascent chain cleavage or rapid posttranslational cleavage of the larger intracellular precursor-like protein, designated Pr110(gag). Pr110(gag) contained all but one of the leucine-containing tryptic peptides of Pr78(gag), plus several additional peptides. In addition to Pr78(gag) and Pr110(gag), monospecific antisera to virion p12 and p25 were also capable of precipitating from pulse-labeled cells a small amount of a 180,000-molecular-weight precursor-like protein, designated Pr180(gag+). This large polyprotein contained nearly all of the leucine-containing tryptic peptides of Pr78(gag) and Pr110(gag) plus several additional peptides. By analogy to type C viral systems, Pr180(gag+) is presumed to represent a gag-pol common precursor which is the major pathway for synthesis of MMTV polymerase. Immunoprecipitation of cytoplasmic extracts from pulse-labeled cells with antisera to gp55 identified two env-specific proteins, designated gPr76(env) and gP79(env). The major env precursor, gPr76(env), could be labeled with radioactive glucosamine and was shown to contain antigenic determinants and tryptic peptides characteristic of gp55 and gp33. A minor glycoprotein, gP79(env), contained both fucose and glucosamine and was precipitable from cytoplasmic extracts with monospecific serum to gp55. It is suggested that gP79(env) represents fucosylated gPr76(env) which is transiently synthesized and cleaved rapidly into gp55 and gp33.