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Biomedical subjects

J A Roth

Publications and source records attributed to J A Roth.

At least 343 records · Page 19Linked to original sources
PubMed1990

Characterization of OKT3-initiated lymphokine-activated effectors expanded with interleukin 2 and tumor necrosis factor alpha.

Synergistic and cooperative effects in vitro of OKT3, interleukin 2 (IL-2), and tumor necrosis factor alpha (TNF) as stimuli in generating effectors with lymphokine-activated killer activity were studied. Activation of human peripheral blood mononuclear cells with OKT3 (10 ng/ml) for 48 h, followed by culture in low concentrations of IL-2 (10 units/ml) and TNF (250 units/ml) resulted in higher cell recovery (50- to 3300-fold) compared to the number of cells in the initial culture and enhanced lytic activity against both Raji and fresh lung tumor targets (mean 100-fold) by day 30 compared to those expanded with higher concentrations of IL-2 (100 units/ml) alone. Immunofluorescence analysis of peripheral blood mononuclear cells initiated with OKT3 and expanded with IL-2 plus TNF revealed a selective increase in CD8+ cells and a decrease in CD4+ by day 28; the opposite effect was observed when cells were incubated with 100 units/ml of IL-2 alone, resulting in a greater proportion of CD4+ cells. Almost all cells were CD3+. Studies of cytokine receptor expression indicated that OKT3 plus IL-2 plus TNF caused an earlier up-regulation of the IL-2 receptor beta chain (Tac) and higher TNF receptor expression by day 6 compared to 100 units/ml IL-2 alone. Significant TNF levels (greater than 17 units/ml) were measured in culture supernatants from peripheral blood mononuclear cells initiated with OKT3 alone. Collectively, our data demonstrate that induction of lymphokine-activated killer activity with OKT3, followed by culture in low concentrations of IL-2 plus TNF is an alternative to the use of high-dose IL-2 alone and suggest that this combination may provide potential advantages in long-term generation of cytolytic cells.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1990

Purification and characterization of human liver phenol-sulfating phenol sulfotransferase.

The phenol-sulfating form of phenol sulfotransferase (P-PST) was purified and characterized from human liver cytosol using DEAE-cellulose, Sephacryl S-200, and 3',5'-diphosphoadenosine-agarose affinity chromatography. During the purification procedure, P-PST was resolved from the monoamine-sulfating form of phenol sulfotransferase (M-PST) and dehydroepiandrosterone sulfotransferase, which are also present in human liver cytosol. P-PST activity was purified 560-fold as compared to liver cytosol and the purified enzyme possessed a specific activity of 340 nmol phenol sulfated per minute per milligram protein. Enzymatically active P-PST has an apparent molecular size of 68,000 Da as determined by Sephacryl S-200 chromatography and a subunit molecular weight of 32,000 Da as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, suggesting that P-PST exists in vivo as a homodimer. Antibodies raised to human platelet M-PST cross-reacted strongly with pure P-PST suggesting the two PSTs are structurally closely related. Two types of P-PST activity have been identified in different human livers by their thermostability and elution during anion-exchange chromatography. Each of the livers examined possessed only one type of P-PST activity. Both types of P-PST were shown to possess the same subunit molecular weight and immunoreactivity, whereas the differences in thermostability of the two P-PST activities appeared to be related to the method of preparation of liver cytosol. Both types of P-PST activity were inhibited to similar extents by incubation with 50 microM N-ethylmaleimide or 5 mM phenylglyoxal. These results suggest that the two types of P-PST in different human livers are very similar and probably represent different allelic forms of the enzyme.

Arylsulfotransferase↗
PubMed1990

Successful combination immunotherapy for the generation in vivo of antitumor activity with anti-CD3, interleukin 2, and tumor necrosis factor alpha.

The purpose of this study was to generate lymphokine-activated killer cells via alternative pathways using combinations of biologic agents. Immunotherapy with the mouse anti-CD3 analogue combined with low-dose interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-alpha) was tested for in vivo antitumor efficacy against established pulmonary metastases from a variety of mouse tumor-cell lines. Administration of a single dose of anti-CD3 followed by low-dose IL-2 and TNF-alpha potentiated reduction of metastases compared with higher doses of IL-2 alone or IL-2 plus TNF-alpha. Treatment with anti-CD3 plus IL-2 plus TNF-alpha significantly prolonged survival and resulted in 60% of the mice achieving long-term survival compared with no survival using single agents or other combinations. The lymphokine-activated killer and natural killer activities of mouse splenocytes increased following treatment with anti-CD3 plus IL-2 plus TNF-alpha. These results indicate that the sequential use of anti-CD3, IL-2, and TNF-alpha for the induction and maintenance of lymphokine-activated killer activity potentiates antitumor activity and provides novel strategies for combination immunotherapy.

Animals↗
PubMed1990

Prognostic indicators in patients with pulmonary metastases.

Pulmonary metastases from different primary neoplasms have different biological characteristics which may correlate with patient survival. Objective criteria to reliably select or exclude patients who would benefit from resection of these metastases are not available; however, various prognostic indicators have been studied for their correlation with post-resection survival. Prognostic indicators differ among various tumor histologies. Prognostic indicators identified preoperatively which may influence post-resection survival include age, sex, histology and location of the primary tumor, tumor doubling time, disease free interval, the number of nodules on preoperative roentgenographic studies, and the number of metastases resected. Following surgery, resectability, and the number of metastases resected may predict expected survival for patients meeting certain criteria. No single criterion should be used to exclude patients from surgery as resection will provide numerous patients with significant post-resection survival.

Age Factors↗
PubMed1990

Survival after surgical resection for high-grade chest wall sarcomas.

Indications for chest wall resection of metastatic or locally recurrent sarcoma and for subsequent bony reconstruction are controversial. Twenty-eight patients had chest wall resection for high-grade primary, metastatic, or recurrent sarcoma. In all patients, resection with selective reconstruction of the bony thorax was performed without operative mortality. Since 1980, only patients with four or more ribs resected have had selective bony reconstruction. Follow-up ranged from 8 to 132 months (median follow-up, 42 months). All deaths were related to sarcoma recurrence. The overall actuarial survival rate was 85% at 1 year, 65% at 3 years, and 59% at more than 5 years. The overall actuarial proportion without disease recurrence was 64% at 1 year, 52% at 3 years, and 40% at more than 5 years. There was no significant difference in overall or disease-free survival for patients with primary, metastatic, or recurrent tumors. The most important prognostic factors were positive margins and concomitant pulmonary resection for synchronous lung metastases. These data support aggressive resection to obtain pathologically tumor-free margins for chest wall sarcomas, whether primary, metastatic or recurrent. Reconstruction can be individualized based on the extent of resection.

Adolescent↗
PubMed1990

Predicted pulmonary function and survival after pneumonectomy for primary lung carcinoma.

Between 1982 and 1987, 139 patients with primary carcinoma of the lung were treated with pneumonectomy. Thirty-nine patients (28%) were in clinical stage I, 10 (7%) were in clinical stage II, and 90 (65%) were in clinical stage III. Overall actuarial 3-year survival was 33%. Actuarial 3-year survival for patients in clinical stage I was 44%; for those in clinical stage II, 48%; and for those in clinical stage III, 28%. Risk factors for operative mortality examined included preoperative forced vital capacity (FVC) of 2.13 L or less and forced expiratory volume in 1 second (FEV1) of 1.65 L or less, percent predicted FVC of 64% or less and FEV1 of 65% or less, predicted postoperative FVC of 1.31 L or less and FEV1 of 0.89 L or less, and predicted postoperative percent predicted FVC of 41% or less and FEV1 of 34% or less. Operative deaths occurred only in clinical stage III patients (7/90 or 8%). Patients with compromised pulmonary function based on one or more of the examined risk factors were at increased risk for death (2/10) compared with patients with better pulmonary function (5/80 or 6.25%). Actuarial 3-year survival for high-risk clinical stage III patients ranged from 0% to 16% compared with 28% for other clinical stage III patients. Thirty-day mortality for pathological stage III patients was 6.3% (5/79), and 3-year actuarial survival was 24%. No patient in pathological stage III who was at high risk survived beyond 3.1 years. Select individuals with adequate pulmonary function and stage III disease can achieve substantial long-term survival after pneumonectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Actuarial Analysis↗
PubMed1990

Model systems to study immunomodulation in domestic food animals.

Development of immunomodulators for use in food producing animals is an active area of research. This research has generally incorporated aspects of immunosuppression in model systems. This methodology is appropriate because most of the research has been aimed at developing immunomodulators for certain economically significant diseases in which immunosuppression is believed to be an important component of their pathogenesis. The primary focus has been on stress-associated diseases (especially bovine respiratory disease), infectious diseases in young animals, and mastitis. The model systems used have limitations, but they have demonstrated that immunomodulators are capable of significantly increasing resistance to these important infectious disease syndromes. As our understanding of molecular immunology increases and as more potential immunomodulators become available, the use of relevant model systems should greatly aid advancement in the field of immunomodulation.

Animals↗
PubMed1990

Chemically induced immunomodulation in domestic food animals.

There is extensive research underway on development of chemical immunomodulators for use in humans. This research is primarily driven by the need for therapeutic immunomodulators for use in patients with cancer or AIDS. Currently, there are no chemicals approved as immunomodulators by the Food and Drug Administration for use in domestic food animals. There is considerable potential for applying the rapid advances in immunomodulation research to benefit domestic animals. In domestic food animals, immunomodulators have the greatest potential for prevention and perhaps therapy in early stages of infectious diseases associated with immunosuppression. There are many different causes for immunosuppression and many different molecular mechanisms responsible for defective function of immune cells. It is unlikely that any one immunomodulator will be capable of preventing or reversing all of these various causes of immunosuppression. Therefore, research is needed to understand the mechanisms of immunosuppression and the mechanism of action of immunomodulators so that rational approaches can be developed for their prophylactic and therapeutic use. Without this information and information on effective dosages and duration of action, attempts to use immunomodulators clinically are likely to produce discouraging results.

Adjuvants, Immunologic↗
PubMed1990

Immunohistochemical detection of phenol sulfotransferase-containing neurons in human brain.

Using antibodies raised against human platelet phenol sulfotransferase (PST), immunohistochemical studies were performed to determine the cellular localization of PST in several areas of human brain. In the hippocampus PST immunoreactivity was localized in both the pyramidal and nonpyramidal neurons and was in greatest abundance in the CA2 and CA3 areas. In the striatum the immunoreactivity was most predominant in the large neurons of the globus pallidus and in the medulla the staining was scattered throughout the neurons of the raphe nucleus and the reticular formation. The selective presence of PST in the neurons of the CNS raises the issue as to the role of this enzyme in sulfating neurotransmitters because PST has been shown to be capable of conjugating a variety of neurotransmitters including the catecholamines as well as the tyrosine moiety of a number of small peptides such as enkephalin and cholecystokinin.

Adult↗
PubMed1990

Daily bedside electrophysiological testing following surgery for the WPW syndrome.

A simple technique is described that allows daily bedside evaluation of the results of surgery for the Wolff-Parkinson-White (WPW) syndrome, using standard postoperative myocardial wires, a single-channel ECG machine, and a temporary pacer capable of rapid stimulation. Rate incremental atrial and ventricular ramp pacing was performed daily in 40 postoperative WPW patients. This technique, together with underdrive pacing in some individuals permits quick assessment of anterograde and retrograde conduction. Two surgical failures were identified in early postoperative days, and promptly returned to the operating room for successful reoperation. No additional failures were identified at formal predischarge electrophysiological testing or following discharge. The technique permits reassurance on a daily basis to apparent successes and early identification in the event of failure, permitting prompt intervention.

Arrhythmias, Cardiac↗
PubMed1990

Evaluation of pre- and postoperative chemotherapy for resectable adenocarcinoma of the esophagus or gastroesophageal junction.

Thirty-five consecutive patients with resectable adenocarcinoma of the esophagus or gastroesophageal junction were treated with two preoperative and three or four postoperative chemotherapy courses consisting of etoposide, fluorouracil, and cisplatin (EFP) to evaluate the rate of curative resection, clinical and pathologic response, toxic effects, and survival. One hundred thirty-seven courses with a median number of five courses (range, one to six) were administered. Preoperative EFP resulted in 17 (49%) major responses, including six patients who did not have carcinoma cells in the repeat endoscopic biopsy specimens and cytologic brushings. Among 32 patients who had surgery, 25 (78%) had curative resection, one patient had a complete pathologic response, and one had microscopic carcinoma in the resected specimen. Six patients had microscopic carcinoma at the resection margins and received postoperative radiotherapy. At a median follow-up of 20 months, the projected survival of 35 patients is 23 months (range, 6 to 33+). Fifteen patients died of their carcinomas, and 15 patients were alive (median follow-up, 20+ months; range, 15+ to 33+ months) with no evidence of relapse. There were no deaths related to chemotherapy, surgery, or radiotherapy. EFP-induced toxic reactions were moderate. Our data suggest that multiple courses of EFP are feasible. Future strategies for this disease should consider prolonged chemotherapy with regimens that result frequently in pathologic complete responses.

Adenocarcinoma↗
PubMed1990

Influence of recombinant bovine interferon gamma and dexamethasone on pneumonia attributable to Haemophilus somnus in calves.

The influence of recombinant bovine interferon gamma (rBoIFN-gamma) treatment on resistance of clinically normal and dexamethasone-treated calves to Haemophilus somnus infection was evaluated. Four groups of 6 calves each were treated with saline solution (controls), dexamethasone (0.04 mg/kg of body weight/for 3 days), rBoIFN-gamma (2 micrograms/kg for 2 days), or dexamethasone and rBoIFN-gamma (aforementioned dosages). All treatments were started 24 hours before intrabronchial challenge exposure with 5 x 10(9) colony-forming units of H somnus. Rectal temperature and WBC count were monitored daily. Two of the dexamethasone-treated calves died of pneumonia 4 days after challenge exposure and were necropsied. All other calves were euthanatized and necropsied 7 days after challenge exposure. All calves had pneumonia of variable intensity. Dexamethasone-treated calves had increased volume of pneumonic lung (P less than 0.05) and increased severity of pneumonia, compared with control calves. Recombinant bovine interferon gamma treatment resulted in reduction in pneumonic lung volume and severity of pneumonia in dexamethasone-treated calves (P less than 0.05), although it did not influence severity of pneumonia in nondexamethasone-treated calves.

Animals↗
PubMed1990

Combination immunotherapy for non-small cell lung cancer. Results with interleukin-2 and tumor necrosis factor-alpha.

Sixteen patients with advanced non-small cell lung cancer were treated with a combination of low-dose interleukin-2 and tumor necrosis factor-alpha. Patients received a continuous 24-hour intravenous infusion of interleukin-2 at 1 X 10(6) Cetus U/m2 and a simultaneous daily intramuscular dose of tumor necrosis factor-alpha (25 to 100 micrograms/m2) for 5 consecutive days. These doses did not have antitumor activity when administered alone in previous trials. Treatment was given at 3-week intervals. Common side effects included fever, local skin reaction at the injection site of tumor necrosis factor-alpha, pancytopenia, and general malaise, all of which were reversible within 48 hours of cessation of therapy. The maximum tolerated doses with this combination were 1 X 10(6) U/m2/day of interleukin-2 and 50 micrograms/m2/day of tumor necrosis factor-alpha, with thrombocytopenia (less than 50K) being the dose-limiting toxicity. Twelve patients received two cycles or more and were evaluable for response. Measurable tumor regression occurred in four patients. An additional seven patients had radiographic stabilization of disease (median = 12 weeks) before progression. All patients had augmented lymphokine-activated killer and natural killer activity during therapy. Enhanced lysis of autologous tumor in vitro was demonstrated in four of four patients during therapy. We conclude that combination immunotherapy with low-dose interleukin-2 and tumor necrosis factor-alpha can mediate tumor regression and can be given with acceptable toxicity.

Adult↗
PubMed1990

Orally administered clonidine as a secretagogue of growth hormone and as a thymotrophic agent in dogs of various ages.

The growth hormone (GH) secretagogue activity of variable dosages of clonidine (16.5, 50, 150, and 450 micrograms/kg of body weight), given orally mixed with the daily food ration, was evaluated in young and old dogs. Significant (P less than 0.05) increase in plasma GH concentration was detected at all dosages tested in young dogs and in response to all but the lowest dose tested in the old dogs fed the clonidine-containing diet. Old dogs had plasma GH concentration that exceeded that of young dogs when higher doses of clonidine were used. A clonidine (100 micrograms/kg)-supplemented diet was fed to middle-aged dogs twice daily for 30 days. Significant (P less than 0.01) increase of plasma GH concentration was observed on the first day of the feeding trial, but was undetectable by day 30. After feeding the clonidine-enhanced diet for 30 days, the effects on thymic morphology were variable, and there was no effect on plasma thymulin titer. Clonidine-fed dogs had significantly increased lymphocyte blastogenic responsiveness to mitogens, compared with that of control dogs, when evaluated as stimulation index.

Administration, Oral↗
PubMed1990

Comparative characterization of the leukocidic and hemolytic activity of Moraxella bovis.

The cytotoxic effect of Moraxella bovis 118F on bovine neutrophils was evaluated and characterized by use of a 51Cr release assay. Neutrophils harvested from healthy adult cattle were labeled with 51Cr. The leukocidic activity produced by M bovis 118F, a hemolytic strain of M bovis, was heat-labile. A live culture of strain 118F, at a ratio of 100 bacteria/neutrophil, released 97.7% of the 51Cr from labeled neutrophils. Neither a heat-killed preparation of M bovis 118F nor a live or heat-killed preparation of M bovis IBH63 (a nonhemolytic and nonpathogenic strain) induced significant (P greater than 0.05) release of 51Cr. Moraxella bovis 118F broth culture filtrates prepared for evaluation of leukocidic activity also were evaluated for hemolytic activity. These 2 toxic activities had several characteristics in common. Both were filterable, heat-labile, produced by a hemolytic strain, and were released during early logarithmic phase growth from broth cultures. Leukocidic and hemolytic activities were protected from degradation by phenylmethyl sulfonyl fluoride, a serine protease inhibitor. Leukocidic and hemolytic activities were dependent on calcium ions. Filtrate resulted in 54.1% 51Cr release from labeled neutrophils and contained 646.7 hemolytic U/ml, respectively, when saline (0.85% NaCl) + 10 mM CaCl2 solution was used as diluent. Neither saline solution nor saline + 10 mM MgCl2 solution supported leukocidic or hemolytic activity. Serum, obtained from several calves 10 to 38 days after M bovis inoculation, substantially neutralized leukocidic and hemolytic activities, compared with paired preinoculation serum samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Influence of recombinant human interleukin-2 administration on lymphocyte and neutrophil function in clinically normal and dexamethasone-treated cattle.

Recombinant human interleukin-2 (rhIL-2) was evaluated for its influence on total and differential WBC counts, lymphocyte blastogenic responsiveness to mitogens, and several measurements of neutrophil function in clinically normal and in dexamethasone-treated cattle. A single dose of rhIL-2 (2.5 X 10(7) U) given SC had no influence on the total or differential WBC count; however, it did cause an inhibition of neutrophil random migration. The other measurements of neutrophil function (Staphylococcus aureus ingestion, cytochrome C reduction, iodination, and antibody-dependent and antibody-independent cell-mediated cytotoxicity) evaluated were not significantly altered. The rhIL-2 treatment was associated with a significant (P less than 0.01) decrease in uptake of [3H]thymidine in unstimulated lymphocytes and a tendency toward enhanced blastogenesis of lymphocytes stimulated with phytohemagglutinin. This enhancement was significant (P less than 0.05) only when the results were expressed as a stimulation index. Lymphocyte responsiveness to concanavalin A and pokeweed mitogen was not significantly influenced by rhIL-2 administration. Dexamethasone (0.04 mg/kg) administered every 24 hours for 3 consecutive days altered the WBC count and several measurements of lymphocyte and neutrophil function. The administration of a single dose of rhIL-2 (2.5 X 10(7) U) 8 hours after the first dose of dexamethasone did not alter the influence of dexamethasone on any of the measurements. These results indicated that rhIL-2 has some biologic activity in cattle, but when used as administered here, did not overcome the influence of dexamethasone on the in vitro measurements of lymphocyte and neutrophil function that were evaluated.

Animals↗