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Biomedical subjects

B H Park

Publications and source records attributed to B H Park.

At least 19 recordsLinked to original sources

Long-term inhibition of tumor growth by tumor necrosis factor in the absence of cachexia or T-cell immunity.

The relationship between detrimental (cachectic) and beneficial (antitumor) effects of tumor necrosis factor (TNF) was studied in mice bearing murine tumors transfected to secrete human TNF. In vitro, the TNF-producing transfectants were resistant to the secreted TNF and grew at rates similar to those of untransfected cells or transfected cells that did not secrete TNF. However, tumors formed by the TNF-secreting cells in vivo remained much smaller than the nonsecreting (transfected and untransfected) tumors. This inhibition of tumor growth required only relatively low serum levels of TNF, persisted for many weeks, and was independent of T cells since it occurred in nude mice. Growth of the TNF-secreting tumors increased dramatically after treatment with anti-human TNF antibody, indicating that extracellular TNF secreted by the tumor cells was necessary for the tumor inhibition. Severe weight loss characteristic of cachexia only occurred in animals with very high serum TNF levels (250 pg/ml) and could be prevented or reversed by anti-TNF antibody treatment. These data are consistent with the existence of a therapeutic window in which persistent exposure to human TNF can lead to prolonged inhibition of tumor growth in the absence of T-cell immunity or severe weight loss and without development of resistant tumor variants.

Animals

A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance.

A highly immunogenic C3H-derived UV-induced tumor was cotransfected with a murine transforming growth factor type beta 1 (TGF-beta 1) cDNA and a neomycin-resistance gene. Stable clones were isolated and used in vitro and in vivo to determine the effects of endogenously produced TGF-beta on cytolytic T-lymphocyte (CTL) responses. Tumor cells producing TGF-beta, though retaining expression for class I major histocompatibility complex molecules and the tumor-specific antigen, did not stimulate primary CTL responses in vitro and were not effective in vivo for directly stimulating primary CTL or in priming for CTL responses. Furthermore, TGF-beta-producing tumors grew progressively in transiently immunosuppressed mice without losing the tumor antigen; thus, TGF-beta produced by tumors may promote escape from immune surveillance.

Animals

The cryptic tetracycline resistance determinant on Tn4400 mediates tetracycline degradation as well as tetracycline efflux.

Escherichia coli containing the cryptic tetracycline resistance determinant (class F) from the Bacteroides fragilis transposon Tn4400 on plasmid pGAT400 expressed a detoxification of tetracycline as well as an active efflux of tetracycline. This finding concurs with the report of detoxification for a related tetracycline resistance determinant from B. fragilis on Tn4351 (B. S. Speer and A. Salyers, J. Bacteriol. 170:1423-1429, 1987), which specifies a 10-fold-higher resistance than Tn4400. Inactivation of tetracycline occurred at an initial rate of congruent to 0.7 micrograms of tetracycline per h per 10(8) cells, as determined by biologic assay and chromatographic analysis. The detoxification is a chemical degradation which can occur in the absence of energy-dependent efflux. The products of this degradation were not substrates for active transport into susceptible cells or out of pGAT400-containing E. coli. These results indicate that Tn4400 mediates two functionally different mechanisms for tetracycline resistance: an active efflux of tetracycline and a degradation of tetracycline.

Escherichia coli

Serum antibodies to cow's milk proteins in ulcerative colitis and Crohn's disease.

Serum antibodies of immunoglobulin G, immunoglobulin M, and immunoglobulin A isotypes to five major proteins of cow's milk, casein, bovine serum albumin, alpha-lactalbumin, beta-lactoglobulin A, and beta-lactoglobulin B, were measured using enzyme-linked immunosorbent assay in 51 patients with ulcerative colitis, 49 with Crohn's disease, and 20 age-matched controls. Immunoglobulin G and immunoglobulin M antibodies to cow's milk proteins were significantly elevated in patients with inflammatory bowel disease as compared to controls. In contrast, no significant increase in immunoglobulin A antibodies to 3 of 5 proteins was noted. The increased titers of antibodies to milk proteins seem to be specific and not due to a polyclonal immunoglobulin activation, as naturally occurring blood group antibodies were not elevated in patients with ulcerative colitis and Crohn's disease. A good correlation of disease activity, as measured by serum alpha 1-acid glycoprotein concentrations, and immunoglobulin G and immunoglobulin A antibody titers against certain cow's milk proteins could be demonstrated in Crohn's disease, but not ulcerative colitis. These findings suggest that production of antibodies to cow's milk proteins reflects specific immunization with these antigens. The study of antibody isotypes and correlation with disease activity may provide better insight into the immune response to dietary antigens and its possible role in the pathogenesis of inflammatory bowel diseases.

Adult

Energy-dependent efflux mediated by class L (tetL) tetracycline resistance determinant from streptococci.

The class L (TetL) tetracycline resistance determinant from streptococci specified resistance and an energy-dependent decreased accumulation of tetracycline in both Streptococcus faecalis and Escherichia coli. Using E. coli, we showed that the reduced uptake resulted from active efflux. The streptococcal class M determinant, known to render the protein synthesis machinery of S. faecalis resistant to tetracycline inhibition, did not alter tetracycline transport in either host.

Energy Metabolism

Cryptic tetracycline resistance determinant (class F) from Bacteroides fragilis mediates resistance in Escherichia coli by actively reducing tetracycline accumulation.

Escherichia coli bearing a cryptic tetracycline resistance determinant from Bacteroides fragilis expressed low-level constitutive resistance to tetracycline under aerobic, but not anaerobic, growth conditions and accumulated less tetracycline aerobically than did isogenic susceptible cells. This decreased uptake was energy dependent and reversible by increased concentrations of tetracycline, suggesting a saturable carrier-mediated active efflux mechanism. Decreased uptake was not seen when the cells were grown and assayed anaerobically. Other tetracycline resistance determinants (classes A to E) isolated from gram-negative enteric bacteria expressed resistance and generated active efflux of tetracycline under anaerobic as well as aerobic conditions. When the Bacteroides determinant was placed in the same cell with any of the class A to E tetracycline resistance determinants, there was an increase in resistance under aerobic conditions of as much as 48% more than was projected by adding the resistances expressed by the determinants individually. In cells bearing the class A determinant together with the Bacteroides determinant, saturation of the active efflux system required over twofold more exogenous tetracycline than did cells bearing the class A determinant alone. We have designated this new tetracycline resistance determinant class F.

Bacteroides fragilis

Defective immunoregulation in children with chronic otitis media with effusion.

Otitis media and middle ear effusions (MEE) are most common clinical problems in early childhood, for which an estimated one million tympanostomies are performed each year in the United States. Although many factors have been associated with MEE (age, sex, genetics, otitis media, socioeconomic status, feeding style, atopy or hypersensitivity, certain bacteria and viruses), a defective immunoregulatory mechanism in the host may also contribute to the pathogenesis. During the past 2 years, we have evaluated immune function in 90 randomly selected children who underwent repeated tympanostomy for persistent MEE. The T-cell subset ratio (OKT-4/OKT-8) was reduced (below 1.25) in 16%. In 33 children, generation of T-cell growth factor (IL-2) by peripheral blood lymphocytes (PBL) was evaluated and found to be decreased in 11. The mitogenic response of PBL to phytohemagglutinin (PHA) and pokeweed mitogen (PWM) stimulation was abnormal in almost half of the cases. Imbalance of T-cell subsets and decreased production of IL-2 indicate defective immunoregulatory function in some of these children, which may play a role in the pathogenesis of persistent MEE.

Adolescent

Adenovirus type 2 encephalitis and concurrent Epstein-Barr virus infection in an adult man.

A 30-year-old bisexual male prisoner with a history of intravenous drug abuse manifested encephalitis. Adenovirus type 2 was isolated from brain tissue obtained by a biopsy and there was a concurrent fourfold rise in the antibody titer. In addition, an initial negative result from a slide test for infectious mononucleosis heterophil antibodies (Monospot) test converted to positive and there was an increase in the IgG antibody titer to Epstein-Barr virus (EBV) viral capsid antigen. Although he was anergic to skin test antigens, T-cell subsets and lymphocyte transformation study results were normal. This case demonstrated a rare adenovirus encephalitis with a simultaneous EBV infection in a patient at risk for acquired immunodeficiency syndrome, who had minimal evidence of T-cell deficiency.

Acquired Immunodeficiency Syndrome

The periodontal microflora of juvenile diabetics. Culture, immunofluorescence, and serum antibody studies.

These studies demonstrate a unique constellation of organisms populating the subgingival area in periodontitis lesions of patients with juvenile or insulin-dependent diabetes mellitus (IDDM). The cultivable microflora was predominated by Capnocytophaga and anaerobic vibrios in the patients studied. In some patients, Actinobacillus actinomycetemcomitans were also found. This distinguishes the subgingival flora of IDDM patients suffering from periodontitis from that of patients with localized juvenile periodontitis (LJP), and that of adult periodontitis patients. In LJP most patients harbor both A actinomycetemcomitans and Capnocytophaga subgingivally; and in periodontitis lesions from nondiabetic adults, black-pigmented Bacteroides such as B gingivalis or B melaninogenicus subspecies intermedius are often found. Antibiotic susceptibility patterns suggest that penicillin or tetracycline or its analogs such as minocycline may be effective against the predominant cultivable microflora in periodontal lesions of IDDM patients; however, individual patients may harbor flora with significant resistance to these antibiotics.

Actinobacillus

IgE and IgD antibodies to cow milk and soy protein in duodenal fluid: effects of pancreozymin and secretin.

Duodenal fluid IgE was reported to be increased in food allergy and in inflammatory conditions of the bowel. We studied the presence and specificity of IgE and IgD antibodies against alpha-casein, beta-lactoglobulin A, alpha-lactalbumin, bovine serum albumin and soy bean agglutinin using an enzyme-linked immunoassay (ELISA). Thirteen children with various intestinal diseases and thirteen normal adult volunteers were examined. In resting duodenal fluids, 8/13 of the children had IgE and 5/13 had IgD, while only 1/13 of the adults showed detectable IgE and IgD. After pancreozymin, 4/6 of the children and 4/8 of the adults showed detectable IgE and IgD in their duodenal fluids. After secretin, the duodenal fluids from 1/8 of the children and 2/8 of the adults had detectable IgE, while 6/13 children and 1/10 of the adults had IgD. The results indicate an increase in duodenal contents of IgE and IgD antibodies specific to cow's milk and soy protein after pancreozymin. Since this mediator is normally released during digestion, it is suggested that IgE and IgD antibodies specific for food proteins, may be involved in the physiological processing of foods in the intestine. In infants and children with gastrointestinal disease, the incidence of IgE and IgD antibodies specific for milk and soy proteins is higher in basal and pancreozymin-stimulated duodenal fluid when compared with control adults.

Adolescent

Pancreozymin and secretin enhance duodenal fluid antibody levels to cow's milk proteins.

Duodenal fluid was collected from normal volunteers before and after stimulation with pancreozymin-cholecystokinin and secretin. Protein content, proteolytic enzyme activities, and antibody activities against cow's milk proteins, alpha-casein, and beta-lactoglobulin B, were measured in the duodenal fluid. After pancreozymin-cholecystokinin stimulation, immunoglobulin A and immunoglobulin M antibody activities rose to peak levels in 5-10 min. The increase in protein content and proteolytic enzyme activities after pancreozymin-cholecystokinin stimulation paralleled the increase in antibody activity against the two cow's milk proteins. Secretin, in spite of its known dilutional effect on duodenal fluid enzyme concentration, also produced a rise in immunoglobulin M and immunoglobulin A antibody activities. Only a slight increase in immunoglobulin G antibody activity was noted after both pancreozymin-cholecystokinin and secretin. It is suggested that, pancreozymin-cholecystokinin and secretin, in addition to their well-established effects on the release of digestive enzymes, also stimulate release of specific antibodies against food proteins. Release of antibody coincident with food intake may act in preventing the inadvertent absorption of antigenic food proteins.

Adult

Effect of Aroclor 1254 on leukocyte glucose uptake.

Uptake of glucose in human leukocytes was estimated by measuring incorporation of 14C-labeled 2-deoxyglucose (2-DG) into the cells. Exposure of lymphocytes and monocytes, but not neutrophils, to Aroclor 1254 (10 microM) caused a decreased 2-DG uptake. This method of measuring glucose uptake may be useful for detecting potential polychlorinated biphenyl (PCB) target cells.

Glucose

Biochemical basis of aroclor 1254 and pesticide toxicity in vitro. 1. Effects on intracellular ATP concentration.

Aroclor 1254 and op'-DDT inhibit lymphocyte mitogenic response to PHA. We use petri dish purified lymphocytes for studying the biochemical basis of chemical toxicity. Aroclor 1254 and DDT decrease lymphocyte intracellular ATP concentration. The inhibitory effect on ATP production is due to the suppression of mitochondrial respiration as judged by decreased oxygen consumption. Lymphocyte glycolysis measured by lactate production is not inhibited by Aroclor 1254 to any significant extent. ATP is required for various biosynthetic reactions following mitogenic stimulation. The inhibition of mitochondrial respiration which leads to decreased ATP concentration may be responsible for Aroclor inhibition of lymphocyte mitogenic response to PHA.

Adenosine Triphosphate

Effects of pesticides on human leukocyte functions.

Aroclor 1254 and twelve pesticides of different chemical classes were tested for their in vitro effects on lymphocyte mitogenic responses to PHA, rosette formation with sheep red blood cells (E-rosette) and neutrophil chemotaxis. By using a diluted whole blood culture, butoxide at 10 micrometers inhibit lymphocyte mitogenic response to PHA by 26%. Inhibition by other pesticides were less than 20% (5--20(). Higher degrees of inhibition were observed if the lymphocytes were pretreated with pesticides in the absence of serum: pp-DDT inhibited by 73% trithion by 50% and benzylthiocyanate by 30%. E-rosette formation was less inhibited by these pesticides except DDT, which inhibited the E-rosette formation by 50% at 10(-4)M. Only methyl parathion was found to have some inhibitory effects on neutrophil chemotaxis. These results indicate that insecticides may have direct effects on the leukocyte function and that the presence of serum may alter the interaction of insecticides and leukocyte membranes.

Chemotaxis, Leukocyte

An improved micro-method for enumeration of human B-cell rosettes with mouse red blood cells.

A micro-method for enumerating B-lymphocytes in human peripheral blood is described, using formation of rosettes with mouse red blood cells as a B-cell marker. The optimal conditions for the enumeration of mouse red cell rosette forming cells have been defined. By this method, it was possible to utilize less than 1ml of peripheral blood (venous or capillary) for simultaneous enumeration of both T-cell and B-cell rosettes. Our study of human lymphoid cell lines, thymic cells, lymphocytes from agammaglobulinemia, and severe combined immunodeficiency has provided additional evidence that lymphocyte rosetting with mouse red blood cells represent B-lymphocytes.

Animals