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Biomedical subjects

J E Harris

Publications and source records attributed to J E Harris.

At least 109 records · Page 6Linked to original sources
PubMed1989

A phase I clinical trial of recombinant interleukin-2 by periodic 24-hour intravenous infusions.

Recombinant interleukin-2 (rIL-2) (NSC# 600664; Hoffmann-La Roche, Inc., Nutley, NJ) was studied in a phase I clinical trial in 33 patients with advanced, measureable cancer of the colon or malignant melanoma, Eastern Cooperative Oncology Group (ECOG) performance status O-1, and no prior chemotherapy or radiotherapy. The goal of the study was to identify a dose and schedule of IL-2 to generate maximal immune modulation with tolerable toxicity. Such a regimen might allow the addition of other treatment modalities and/or prolonged treatment duration in later trials. Each patient received IL-2 as a continuous 24-hour infusion once weekly for 4 weeks and then twice weekly for 4 weeks. Five treatment groups received from 10(3) U/m2 to 3 x 10(7) U/m2 per 24-hour infusion. The maximal tolerated dose was 3 x 10(7) U/m2/d twice weekly. Patients treated twice weekly at 1 x 10(7) and 3 x 10(7) U/m2/d had immune modulation in terms of lymphocytosis, eosinophilia, increased natural killer (NK) activity, and elevated numbers of peripheral blood mononuclear cells expressing CD16, OKT10/Leu-17, and Leu-19 surface markers. Endogenous generation of peripheral blood lymphokine-activated killer (LAK) activity was demonstrated by lysis of NK-resistant Daudi targets, in patients treated at 3 x 10(7) U/m2/d. Biochemical and hematological abnormalities were moderate and reversible. Clinical toxicity included hypotension, myalgia, arthralgia, stomatitis, fever, fatigue, nausea, headache, chills, diarrhea, and oliguria at high doses. Cardiovascular toxicity was tolerable for most patients and reversed after IL-2 was stopped. Two of six melanoma patients at 3 x 10(7) U/m2/d achieved partial responses by the end of the eighth week. This IL-2 schedule appears to produce potentially clinically useful immune enhancement with tolerable toxicity.

Adolescent↗
PubMed1989

Effect of nordihydroguaiaretic acid on cultured rat and human glioma cell proliferation.

When cultured malignant cells derived from rat gliomas (C6 and 9L) and human gliomas (A-172 and T98G) were treated for 4 hours with 1 to 80 microns nordihydroguaiaretic acid (NDGA) or 5,8,11,14-eicosatetraynoic acid (ETYA), a dose-dependent inhibition of deoxyribonucleic acid (DNA) synthesis occurred. In a series of three experiments for each cell line, 40 microM NDGA suppressed 3H-thymidine incorporation in the rat and human glioma lines to an average of less than 3.1% and 5.6% of control uptake (counts per minute), respectively. Incubation with a higher concentration of ETYA (80 microM) resulted in inhibition of rat and human DNA synthesis to less than 53% and 62% of control levels, respectively. This inhibition was not associated with any loss of cell viability, as judged by trypan blue exclusion studies. Prolonged incubation (for 72 hours) of the rat and human glioma cells with NDGA markedly decreased cell proliferation with no loss of cell viability. The inhibition of human glioma cell division by NDGA was rapidly reversible after incubation for 24 hours and at least partially reversible after incubation for 96 hours. It is concluded that the inhibitors of eicosanoid biosynthesis, NDGA and (to a lesser extent) ETYA, reduce in vitro cell proliferation in two glioma lines from both the rat and human. Since neither indomethacin nor acetylsalicylic acid altered DNA synthesis in these cell lines, this implicates the lipoxygenase products of arachidonic acid metabolism as important positive modulators in glioma cell division. These findings warrant further study in an in vivo system.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1988

Labelling of lipids and phospholipids with [3H]arachidonic acid and the biosynthesis of eicosanoids in U937 cells differentiated by phorbol ester.

Phorbol esters induce morphologic and biochemical differentiation in U937 cells, a monocyte/macrophage-like line derived from a human histiocytic lymphoma. We are interested in the phorbol ester-stimulated release of arachidonic acid from cellular membranes and the subsequent synthesis of eicosanoids, as it may prove to correlate with the induced cellular differentiation. Undifferentiated log-phase U937 cells released little recently incorporated [3H]arachidonic acid, but phorbol 12-myristate 13-acetate increased its apparent rate of release to that of cells differentiated by exposure to phorbol myristate acetate for 3 days. Exposure of washed differentiated cells immediately prelabelled with [3H]arachidonic acid to additional phorbol myristate acetate did not augment the release of [3H]arachidonic acid. The basal release of nonradioactive fatty acids from differentiated cells was 5-10 times that of undifferentiated cells, and phorbol myristate acetate increased their release from both types of cell 2- to 3-fold. Differentiated cells immediately prelabelled with [3H]arachidonic acid exhibited greater incorporation into phosphatidylinositol and phosphatidylcholine, and contained more radioactive free arachidonic acid, compared with undifferentiated cells. Undifferentiated cells contained more radioactivity in phosphatidylserine, phosphatidylethanolamine and neutral lipids. Phorbol myristate acetate caused differentiated cells to release [3H]arachidonic acid from phosphatidylinositol, phosphatidylserine, phosphatidylcholine and phosphatidylethanolamine, but release from neutral lipids was reduced, and the content of [3H]arachidonic acid increased. In undifferentiated cells incubated with phorbol myristate acetate, radioactivity associated with phosphatidylserine, phosphatidylethanolamine and neutral lipid was reduced and [3H]arachidonic acid was unchanged. Synthesis of cyclooxygenase products exceeded that of lipoxygenase products in both differentiated and undifferentiated cells. Phorbol myristate acetate increased the synthesis of both types of product, cyclooxygenase-dependent more than lipoxygenase-dependent, especially in differentiated cells. The biological significance of these changes in lipid metabolism that accompany phorbol myristate acetate-induced differentiation are yet to be established.

Arachidonic Acid↗
PubMed1988

In vivo effects of recombinant IL-2. I. Isolation of circulating Leu-19+ lymphokine-activated killer effector cells from cancer patients receiving recombinant IL-2.

This study was designed to isolate and phenotypically characterize lymphokine-activated killer (LAK) cells generated in vivo during administration of high dose rIL-2 to cancer patients. The development of circulating LAK effector cells in these patients was demonstrated by the ability of fresh PBL to exhibit lytic activity against the NK-resistant Daudi cell line and fresh tumor cells without prior in vitro culture with rIL-2. Kinetic studies demonstrated that circulating LAK effector cells are detectable 4 to 6 wk after the initiation of rIL-2 therapy. Cells isolated by FACS revealed that circulating LAK cells are Leu-19+, Leu-17+ but CD5-. We have previously reported that circulating Leu-19+ cells are heterogeneous with regard to the expression of CD16 and CD8. Since sorting of cells expressing Leu-19 and either low quantities of CD8 or CD16 resulted in cytolytic activity in both the positive and negative fractions, these latter two markers do not identify subpopulations of Leu-19+ cells with or without LAK cytolytic activity. Although all LAK cells generated in vivo were Leu-19+, we generated LAK cells from the Leu-19- subpopulation after in vitro culture with rIL-2, suggesting that at least some of in vitro generated LAK cells are derived from Leu-19- precursor cells. These LAK cells did not, however, express the Leu-19 surface marker. Based on the functional data reported in this paper, we conclude that circulating LAK effector cells are a phenotypically heterogeneous population that express surface Ag in association with NK cells and not T lymphocytes.

Antigens, Neoplasm↗
PubMed1988

Paleoradiologic evaluation of the Egyptian royal mummies.

We examined radiographs of 12 Egyptian royal mummies obtained by two of the authors (W.R. and J.E.H.) and never before published. These radiographs demonstrate findings not previously described in Egyptian mummies, including congenital lunate-triquetral fusion and destructive skeletal lesions not explainable on the basis of vandalism by tomb robbers. Antemortem fractures, degenerative joint disease, and arterial vascular calcification were also seen. In 11 of the 12 cases, there was chondrocalcinosis of intervertebral discs or menisci, probably an artifact of embalming. Visceral packing and skeletal deformity due to wrapping were observed, as well. Radiology provides important paleopathologic and archeologic information for the accurate, comprehensive study of Egyptian mummies.

Bone Diseases↗
PubMed1988

Monocyte functional studies in asymptomatic, human immunodeficiency disease virus (HIV)-infected individuals.

Various aspects of monocyte-associated function were evaluated in the peripheral blood mononuclear cells of male homosexuals who were infected with the human immunodeficiency disease virus (HIV). The functional assessments included indomethacin-sensitive regulation of blastogenesis and lymphokine-activated killer (LAK)-cell induction, chemiluminescent responses of mononuclear leukocytes to opsonized zymosan, and the expression of HLA-DR antigen on CD-14-positive monocytes. The results obtained demonstrate that each of these functions is abnormal in asymptomatic individuals who have HIV core antigen (p24) in their circulation. These results suggest that monocyte abnormalities which could contribute to immune dysfunction in HIV-infected patients can be detected early during the course of HIV infection and are associated with the expression of serum HIV antigen.

HIV Core Protein p24↗
PubMed1988

Gut immunology in fish: a review.

During recent years considerable study has been made of the systemic immune system of fish, although less attention has been paid to local immunity at sites such as the gut, reproductive tract and skin. Recent work on the structure of gut-associated lymphoid tissue and other intestinal cell populations, the absorption of macromolecules from the intestinal lumen and the production of specific mucosal antibodies strongly suggests, however, that the gut of these lower vertebrates is immunocompetent. This review briefly deals with current concepts on the nature of gut-associated lymphoid tissues and other cell populations in the gut, intestinal and biliary immunoglobulin (Ig), antigen uptake and the significance of oral vaccination in the protection of commercially reared fish against infectious disease.

Administration, Oral↗
PubMed1988

Synthesis of hepatic protein during pregnancy in the rat.

The accumulation of hepatic protein during pregnancy in the rat could be the result of a decrease in rate of degradation, an increase in rate of synthesis or both. The purpose of the study was to determine relative rates of synthesis of hepatic protein for pregnant and nonpregnant rats. Pregnant and nonpregnant Sprague-Dawley rats were fed a 20% casein, purified diet from the first day of gestation. On d 19 of gestation the rats were killed. Livers were weighed and assayed for RNA. Relative synthesis rates of hepatic protein were assessed by homologous in vitro cell-free translation. RNA per liver and per g liver and incorporation of labeled leucine into protein per liver and per unit of RNA were greater for the pregnant rats than the nonpregnant rats. In conclusion, accumulation of hepatic protein during pregnancy is at least partially the result of an increase in rate of synthesis.

Animals↗
PubMed1988

A simple chromatographic procedure for the detection of cyclized archaebacterial glycerol-bisdiphytanyl-glycerol tetraether core lipids.

Archaebacterial glycerol-bisdiphytanyl-glycerol tetraether core lipids containing from one to eight cyclopentane rings could be resolved from each other and from the parent uncyclized C40, C40 lipid by TLC. The core lipids of examples from the genera Methanobacterium, Methanobrevibacter, Methanogenium and Methanoplanus did not contain cyclized forms of glycerol-bisdiphytanyl-glycerol tetraethers, whereas the core lipids of Methanosarcina barkeri contained glycerol-bisdiphytanyl-glycerol tetraethers with from one to three cyclopentane rings in each C40 isopranoid chain.

Archaea↗
PubMed1988

Characterization of antigenic determinants in histoplasmin that stimulate Histoplasma capsulatum-reactive T cells in vitro.

Although antigen-reactive T lymphocytes play a central role in the host response to Histoplasma capsulatum, little is known of the nature of Histoplasma antigens recognized by these cells in vitro. Employing a murine T-cell line and two clones that are reactive with histoplasmin, we examined whether activation of T cells by histoplasmin required the presence of carbohydrate or protein moieties. The approach taken was to modify carbohydrate or protein molecules in histoplasmin by chemical or enzymatic digestion or by lectin adsorption. In parallel, antigen was subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis to correlate alterations in functional activity with changes in the electrophoretic appearance of histoplasmin. Treatment of histoplasmin with periodate (0.1 M, 0.05 M, and 0.01 M) or with the endoglycosidases N-glycanase and endoglycosidase H sharply diminished the capacity of histoplasmin to trigger responses by T cells. Reactivity of T cells to histoplasmin that had been adsorbed with lectins binding mannose, glucose, or galactose was reduced by greater than 70%; conversely, the responses by T cells to antigen that had been adsorbed with lectins specific for fucose, N-acetylgalactosamine, or N-acetylglucosamine ranged from 82 to 91% of that to control antigen. Proliferative responses by T cells to histoplasmin that had been digested with chymotrypsin, protease, or trypsin were 2 to 43% of control values. The electrophoretic appearance of histoplasmin was modified by some but not all of the treatments. Partially purified H and M antigens triggered proliferation of T cells. Thus, both carbohydrates and proteins must be present to induce optimal responses by T cells. A portion of the carbohydrates is N linked to proteins, and alpha-D-mannose (or alpha-D-glucose) and beta-D-galactose are the sugar ligands of carbohydrate-containing antigens.

Adsorption↗
PubMed1987

Clinical evaluation of efficacy, pharmacokinetics, and safety of teicoplanin for serious gram-positive infections.

Nineteen patients hospitalized for serious gram-positive infections were treated with teicoplanin, a new glycopeptide antibiotic. A variety of infections were treated, including endocarditis, septic thrombophlebitis, osteomyelitis, pyogenic arthritis, and soft tissue infection. Of 13 infections that could be evaluated in 12 patients, there were 8 clinical cures, 2 improvements, 1 recurrence, and 2 failures. Of the eight patients with Staphylococcus aureus bacteremia, seven were clinically cured or improved with teicoplanin therapy. Of the nine patients in whom the bacteriological response to treatment could be fully evaluated, six were cured; there was recurrence of infection in one, and treatment failed in two patients. In vitro testing showed the 13 bacterial isolates (9 S. aureus, 3 S. epidermidis, and 1 group B streptococcus) to be uniformly susceptible to teicoplanin, with MICs ranging from 0.12 to 0.5 microgram/ml. Every isolate was more susceptible in vitro to teicoplanin than to vancomycin. Three of the staphylococcal isolates were resistant to methicillin. Pharmacokinetic studies demonstrated that after an initial drug-accumulation period, a single daily dose adequately maintained the teicoplanin concentrations in serum within therapeutic ranges. Teicoplanin also penetrated well into synovial fluid. The drug was well tolerated by either intravenous or intramuscular administration. The most significant adverse reaction was an urticarial rash which required discontinuation of therapy in one patient; a second patient experienced a modest decrease in high-frequency auditory threshold. Asymptomatic eosinophilia and mild elevation of serum transaminases were noted as well. The results of this study suggest that teicoplanin is a safe and effective new agent for treatment of serious infections caused by gram-positive organisms.

Adult↗
PubMed1987

Spontaneous Disaggregation of Methanosarcina mazei S-6 and Its Use in the Development of Genetic Techniques for Methanosarcina spp.

When monomethylamine was the growth substrate, spontaneous disaggregation of Methanosarcina mazei S-6 commenced at the mid-exponential phase and resulted in the formation of a suspension containing 10 to 10 free cells per ml. Free cells were osmotically fragile and amenable to extraction of DNA. Hypertonic media for the manipulation and regeneration of free cells into aggregates were developed, and plating efficiencies of 100% were achieved for M. mazei S-6 and LYC. Free cells of strain S-6 required MgCl(2) (10 mM) for growth, whereas aggregates did not. Specific growth rates of strains S-6 and LYC were increased by MgCl(2). Treatment with pronase caused sphere formation and removal of the protein wall of cells of strain S-6, but protoplasts could not be regenerated. The disaggregating enzyme produced by strain S-6 facilitated the preparation of suspensions of free cells of some strains of Methanosarcina barkeri. Although this provided a means of extracting high-molecular-weight DNA from M. barkeri, less than 0.1% of free cells were viable.

Journal Article↗