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Biomedical subjects

J F Warner

Publications and source records attributed to J F Warner.

18 recordsLinked to original sources
PubMed1991

Induction of HIV-specific CTL and antibody responses in mice using retroviral vector-transduced cells.

Recombinant retroviral vectors can efficiently transduce and express foreign genes in mammalian cells. We have examined the utility of retroviral vector-mediated gene transfer to deliver genes which encode human immunodeficiency virus type I (HIV) antigens capable of stimulating specific immune responses. Murine fibroblast cell lines were transduced with a nonreplicating murine retroviral vector carrying the gene encoding the HIV-IIIB envelope protein and were shown to express the gp160/120 protein. Mice immunized with syngeneic vector-transduced cells developed CD8+, class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) specific for targets expressing the HIV envelope protein. The CTL also exhibited lytic activity on target cells coated with synthetic peptides derived from the gp120 V3 hypervariable region of both the HIV-IIIB and HIV(MN) isolates. Following adoptive transfer in a murine tumor model, these CTL were shown to be effective in vivo by their ability to eliminate established tumor cells expressing the HIV protein. Vector-transduced syngeneic cells were also capable of eliciting HIV envelope-specific antibody responses in immunized mice. Sera obtained from these mice were found to bind to the HIV-IIIB gp160 protein as well as a peptide-defined neutralizing antibody epitope contained within the V3 domain of gp120. These sera exhibited virus-neutralizing activity in that they markedly reduced the ability of HIV to infect and form syncytia of a human T-cell line. This is the first demonstration that cells transduced with a retroviral vector encoding the HIV-IIIB envelope protein are capable of inducing effective HIV-specific cellular and humoral immune responses in mice.

Amino Acid Sequence↗
PubMed1991

Induction of anti-HIV-1 immune responses by retroviral vectors.

Retroviral vectors encoding HIV-1 proteins, in particular, the envelope from HIV-1 IIIB, have been constructed and used to generate infectious vector particles. Murine cells transduced with these vectors express HIV proteins. Vector-transduced cells, when injected into syngeneic BALB/c mice, induce potent CD8+, class I MHC-restricted cytotoxic T-lymphocyte responses and elicit the production of neutralizing antibody specific for HIV-1. The induction of similar responses in primates may provide the basis for considering the use of these vectors as immunostimulants in humans. The retroviral vectors or vector-transduced cells would probably be first employed as an immunotherapeutic for HIV-infected individuals.

Animals↗
PubMed1990

Neuroleptic malignant syndrome associated with prochlorperazine.

Neuroleptic malignant syndrome occurred in a patient with AIDS being treated with prochlorperazine. We believe this to be the first report of this association. Recognition and specific treatment were delayed in part because of overlap in signs and symptoms of the underlying infectious process. The true incidence of prochlorperazine-induced NMS is unknown, and this reaction may be underrecognized in patients who often have other significant medical illnesses.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Retroviral vectors as vaccines and immunotherapeutics.

Retroviral vectors have been tested in mice for their ability to induce immune response to the proteins which their genomes encode. Using HIV encoded proteins as a model, potent cytotoxic T lymphocyte (CTL) and antibody responses are seen to these proteins. This apparent efficacy of induction may be due to the relative simplicity of the vector and the manner in which antigens are presented to the immune system. Safety issues and other proposed methods of CTL induction are discussed. The potential application of retroviral vectors as immune stimuli in man seems quite broad (viral diseases and cancer), and the first attempted applications in man are likely to be therapeutic rather than prophylactic.

Genetic Vectors↗
PubMed1985

Bone marrow graft rejection as a function of antibody-directed natural killer cells.

There is conclusive evidence that acute bone marrow transplant rejection in lethally irradiated mice is caused by natural killer (NK) cells. The rejection of marrow allografts is exquisitely specific and is controlled by antigenic determinants encoded in or near the H-2 gene complex. The specificity of in vivo marrow graft rejection contrasts with the in vitro specificity pattern of NK cells in cytotoxicity assays. We therefore examined how NK cells cause H-2-specific marrow graft rejection in vivo. Several experimental approaches are presented that suggest that natural antibody, present in responder strains of mice, specifically directs NK cells in an antibody-dependent cytolytic and/or cytostatic reaction, resulting in marrow graft rejection. The following evidence for this mechanism is documented. The ability to reject a marrow graft can be passively transferred by serum from responder to allogeneic nonresponder mice and the specificity of rejection can be mapped within the H-2 region. Serum-induced marrow graft rejection is abrogated following depletion of immunoglobulin, and the serum of responder mice is able to induce a specific antibody-dependent cytotoxic reaction in vitro.

Animals↗
PubMed1985

Adoptive transfer studies demonstrating the antiviral effect of natural killer cells in vivo.

We carried out adoptive transfer studies to determine the role of natural killer (NK) cells in resistance to murine cytomegalovirus (MCMV) and lymphocytic choriomeningitis virus (LCMV). We transferred leukocytes from adult mice into suckling mice 1 d before injecting them with virus. Resistance was measured by enhancement of survival and reduction of virus multiplication in the spleens of recipient mice. The phenotype of the cell population capable of mediating resistance to MCMV was that of a nylon wool-nonadherent, asialo GM1+, NK 1.2+, Ly-5+, Thy-1-, Ia-, low density lymphocyte; this is the phenotype of an NK cell. Cloned NK cells, but not cloned T cells, provided resistance to MCMV in suckling mice. Cloned NK cells also provided resistance to MCMV in irradiated adult mice, and antibody to asialo GM1, which depletes NK cell activity in vivo, enhanced the synthesis of MCMV in athymic nude mice. Neither adult leukocytes nor cloned NK cells influenced LCMV synthesis in suckling mice. We conclude that a general property of NK cells may be to provide natural resistance to virus infections, and that NK cells can protect mice from MCMV but not from LCMV.

Aging↗
PubMed1979

A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis.

We compared amphotericin B therapy for cryptococcal meningitis with a newer regimen containing both amphotericin B and flucytosine. In 50 patients with 51 courses of therapy adherent to the protocol, 27 courses were with amphotericin B and 24 with the combination. Even though the combination regimen was given for only six weeks and amphotericin B for 10 weeks, the combination cured or improved more patients (16 vs 11), produced fewer failures or relapses (three vs. 11), more rapid sterilization of the cerebrospinal fluid (P less than 0.001) and less nephrotoxicity (P less than 0.05) than did amphotericin B alone. The number of deaths was the same (five) with each regimen. Adverse reactions to flucytosine occurred in 11 of 34 patients but were not life threatening. We conclude that combined flucytosine-amphoericin B therapy is the regimen of choice in cryptococcal meningitis.

Adolescent↗
PubMed1979

Metronidazole therapy of anaerobic bacteremia, meningitis, and brain abscess.

Four patients with Bacteroides fragilis bacteremia, one patient with a brain abscess due to Bacteroides species, Fusobacterium naviforme, and Peptostreptococcus species, and an infant with Bacteroides species ventriculitis and meningitis were treated with metronidazole. In all cases the anaerobic pathogens were eradicated. Five of the six patients recovered. One patient with leukemia in whom B fragilis bacteremia was eradicated by metronidazole treatment subsequently died of Pseudomonas aeruginosa bacteremia. Ventricular fluid and serum concentrations of metronidazole were determined in the case of meningitis and are reported.

Adult↗
PubMed1979

F1 hybrid anti-parental H-2k cell-mediated lympholysis. I. Stimulator and target determinants controlled by the H-2K region.

H-2k-heterozygous F1 hybrid mouse spleen cells cultured with irradiated H-2k-homozygous stimulator cells generated specific anti-parent cytolytic effectors. The parental antigenic determinants recognized by responder cells during induction (afferent arm) and by effector cells during cytolysis (efferent arm) were coded for, or regulated by, the H-2K-Hh3 region of the MHC, according to recombinant analysis. There were no detectable influences by other linked or unlinked genes on the phenotypic expression of parental antigens; however, the anti-parent responsiveness was modulated by background genes of responder cells. These experiments establish that the K end of H-2 controls determinants of F1 anti-parental H-2k CML, like the D end controls those of F1 anti-parental H-2b CML, thus confirming the basic symmetry of the H-2 complex. The relationship of this primary in vitro cell-mediated response with natural in vivo resistance to parental and allogeneic bone marrow grafts is discussed.

Animals↗
PubMed1977

Effects of Fusobacterium necrophorum leukotoxin on rabbit peritoneal macrophages in vitro.

A method to demonstrate leukotoxic activity of Fusobacterium necrophorum in vitro is described. Continuous dialysis sac culture system, using reduced liquid medium was used to grow F necrophorum for 7-day periods. The continuous culture dialysis filtrate contained leukotoxic substance(s) which appeared to be less than 10,000 in molecular weight, heat resistant, and stable at 4 C for at least 10 days. Leukotoxic activity was demonstrated in vitro by determining the percentage of macrophages taking up trypan blue dye after these were exposed to a 1:2 solution of continuous culture dialysis filtrate and Eagle's minimal essential medium at 1, 2, 4, and 6 hours. Approximately 90% of these macrophages were destroyed during the 6-hour incubation period.

Animals↗
PubMed1976

Nafcillin treatment of Staphylococcus aureus meningitis.

Serial serum and cerebrospinal fluid nafcillin concentrations were determined in a patient successfully treated with nafcillin (200 mg/kg per day) for Staphylococcus aureus bacteremia and meningitis. Nafcillin and methicillin cerebrospinal fluid concentrations were compared.

Aged↗
PubMed1975

Therapy of cryptococcosis with a combination of flucytosine and amphotericin B.

In a prospective study from May 1971 to November 1973, 20 consecutive patients with a diagnosis of disseminated cryptococcosis were treated for six weeks with a combination of amphotericin B (20 mg daily) intravenously and flucytosine (150 mg/kg daily) orally. Fifteen patients has culturally docummented Cryptococcus neoformans meningitis, and three died of infection early in therapy. Of the remaining 12 patients, eight were alive and well eight to 34 months after therapy, and four died of other causes. None of the surviving patients has relapsed. Hematologic complications developed in nine patients, three of whom had no underlying lymphoreticular disorder or therapy with known cytotoxic agents. Renal insufficiency of mild degree occurred in only six patients. A shorter period of hospitalization and reduction in toxicity of amphotericin B suggest that combined therapy is a safe and efficacious alternative to other regimens.

Adult↗
PubMed1975

Endotoxin from Fusobacterium necrophorum of bovine hepatic abscess origin.

The endotoxic activity of Fusobacterium necrophorum bov 5 was investigated. The supernatant (S) fluid and cell wall (CW) preparation, obtained after differential centrifugation of the ruptured cell mass, were lethal for mice. The toxicity of the S fluid was stable during prolonged storage, treatment with formalin, and heating for 15 minutes at 80, 100, and 121 C, but was destroyed by alkaline hydrolysis with 0.25 N NaOH. The toxic factor was found in a high molecular weight (MW) fraction after gel filtration. The properties exhibited by the toxic S fluid resembled those of endotoxic lipopolysaccharide (LPS). Extracted and partially purified LPS (endotoxin) from F necrophorum bov 5 demonstrated a mouse median lethal dose (mouse LD50) of 16.8 mg/kg of body weight. The toxic LPS material, a high molecular weight moiety as estimated by gel filtration, was resistant to ribonuclease (RNase), deoxyribonuclease (DNase), and pronase treatment. A positive Shwartzman reaction (median skin lesion dose (SLD50) equal to 3.32 mug/kg of body weight) and biphasic fever response (minimal dose required to produce a fever index of 40 sq cm which falls on the linear portion of dose-response curve (FL40) equal to 0.41 mug/kg of body weight) further indicated the toxin was endotoxin in nature. The LPS from F necrophorum bov 5 was less toxic than Salmonella typhimurium LPS; but had considerable toxicity for experimental animals. The toxic activity of the partially purified F necrophorum bov 5 endotoxin was separated into 2 fraction regions by diethylaminoethyl (DEAE)-cellulose chromatography. The data provide evidence for the production of a potent endotoxin, possibly composed of more than one toxic component, which may be released upon cell disruption.

Animals↗
PubMedDate not supplied

Therapy of skin, soft tissue, and bone infections with cefoxitin sodium.

Twenty-seven patients with skin and soft tissue infections, including three with contiguous osteomyelitis, were given cefoxitin intravenously or intramuscularly; the infections of 25 (93%) were resolved with cefoxitin therapy. Etiologic agents included staphylococci, streptococci, Enterobacteriaceae, and anaerobes. Susceptible pathogens were inhibited by less than or equal to 8 micrograms of cefoxitin/ml. This level of drug was surpassed by mean peak serum concentrations eight- to 12-fold after intravenous infusions and two- to threefold after intramuscular injections and resulted in eradication of susceptible organisms from lesions during treatment. Intravenously administered cefoxitin was well tolerated, although eosinophilia, phlebitis, elevation of levels of hepatic enzymes, and a positive direct Coombs' test were observed. Intramuscular injections of cefoxitin in 0.5% lidocaine caused pain and induration and thus were poorly tolerated.

Abscess↗
PubMedDate not supplied

Infected subfural hematoma: three case reports involving gram-negative organisms.

Three case reports of infected subdural hematoma are presented, two with Salmonellae and one with Escherichia. Infection of such hematomas most often occurs during bacteremia, and the area of infection is limited by the existing hematoma membrane. Clincally, fever, headache, nuchal rigidity, and focal neurological signs, especially in a patient with previous head trauma, suggest subdural infection. Treatment consists of drainage and systemic antibiotics. These case reports demonstrate the clinical features of this rarely reported entity, and especially illustrate the need for careful bacteriologic identification in suspected cases.

Adult↗