Psychological implications of chemical and biological weapons.
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Anxiety↗
Biomedical subjects
R Bartholomew
Publications and source records attributed to R Bartholomew.
TCR peptide therapy in human autoimmune diseases.
Inflammatory Th1 cells reacting to tissue/myelin derived antigens likely contribute to the pathogenesis of diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), and psoriasis. One regulatory mechanism that may be useful for treating autoimmune diseases involves an innate second set of Th2 cells specific for portions of the T cell receptor of clonally expanded pathogenic Th1 cells. These Th2 cells are programmed to respond to internally modified V region peptides from the T cell receptor (TCR) that are expressed on the Th1 cell surface in association with major histocompatibility molecules. Once the regulatory Th2 cells are specifically activated, they may inhibit inflammatory Th1 cells through a non-specific bystander mechanism. A variety of strategies have been used by us to identify candidate disease-associated TCR V genes present on pathogenic Th1 cells, including BV5S2, BV6S5, and BV13SI in MS, BV3, BV14, and BV17 in RA, and BV3 and BV13S1 in psoriasis. TCR peptides corresponding to the mid region of these BV genes were found to be consistently immunogenic in vivo when administered either i.d. in saline or i.m. in incomplete Freund's adjuvant (IFA). In MS patients, repeated injection of low doses of peptides (100-300 microg) significantly boosted the number of TCR-reactive Th2 cells. These activated cells secreted cytokines, including IL-10, that are known to inhibit inflammatory Th1 cells. Cytokine release could also be induced in TCR-reactive Th2 cells by direct cell-cell contact with Th1 cells expressing the target V gene. These findings indicate the potential of regulatory Th2 cells to inhibit not only the target Th1 cells, but also bystander Th1 cells expressing different V genes specific for other autoantigens. TCR peptide vaccines have been used in our studies to treat a total of 171 MS patients (6 trials), 484 RA patients (7 trials), and 177 psoriasis patients (2 trials). Based on this experience in 824 patients with autoimmune diseases, TCR peptide vaccination is safe and well tolerated, and can produce significant clinical improvement in a subset of patients that respond to immunization. TCR peptide vaccination represents a promising approach that is well-suited for treating complex autoimmune diseases.
Arthritis, Rheumatoid↗
Pokémon contagion: photosensitive epilepsy or mass psychogenic illness?
We studied a reported illness outbreak occurring on December 16, 1997, involving more than 12,000 Japanese children who had various signs and symptoms of illness after watching an episode of a popular animated cartoon, Pokémon. While photosensitive epilepsy was diagnosed in a minuscule fraction of those affected, this explanation cannot account for the breadth and pattern of the events. The characteristic features of the episode are consistent with the diagnosis of epidemic hysteria, triggered by sudden anxiety after dramatic mass media reports describing a relatively small number of genuine photosensitive-epilepsy seizures. The importance of the mass media in precipitating outbreaks of mass psychogenic illness is discussed.
Child↗
Epidemic hysteria in Virginia: the case of the phantom gasser of 1933-1934.
OBJECTIVE: We studied an example of epidemic hysteria occurring outside a closed community and involving fear of being "gassed." The description presented is that of a previously unrecorded case of epidemic hysteria in the state of Virginia during 1933-1934. DATA SOURCES: Data were gathered from contemporary newspaper accounts. CONCLUSION: The case of the Virginia "gasser" is one in a long series of epidemic hysteria incidents during the 20th century, coinciding with heightened awareness of environmental pollution and triggered by imaginary or exaggerated contamination threats. A recommendation is provided on how physicians should approach such episodes.
Conversion Disorder↗
Phase I and imaging trial of a monoclonal antibody directed against gastrin-releasing peptide in patients with lung cancer.
Small cell lung cancer (SCLC) cells express and secrete bombesin-like peptides (BLP) that can activate specific receptors that stimulate the growth of these cells. A murine monoclonal antibody, 2A11, which binds to the BLP, gastrin-releasing peptide with high affinity, has been reported to decrease the growth of SCLC cells in vitro and in athymic nude mice. A Phase I trial in lung cancer patients was performed using multiple doses of 2A11. Thirteen patients with lung cancer received 12 doses of 2A11 antibody three times a week for 4 weeks at one of four dose levels. Serum samples were obtained prior to initiation and before each dose of 2A11 antibody therapy for measurement of 2A11 antibody levels and determination of serum human anti-mouse antibody levels. A pilot imaging evaluation using 111In conjugated 2A11 monoclonal antibody was also performed in the same patients to aid in the study of pharmacokinetics and biodistribution. No toxic reactions were observed, and none of the patients developed detectable human antimouse antibody; however, no objective antitumor responses were observed. The mean trough serum 2A11 levels in patients increased with increasing dose level: 0.26+/-0.2 microg/ml, 6.7+/-6 microg/ml, 71.5+/-60 microg/ml, 248+/-184 microg/ml for dose levels 1 mg/m2, 10 mg/m2, 100 mg/m2, and 250 mg/m2, respectively. At each dose level, sustained detectable serum levels of the monoclonal antibody were achieved. Tumor uptake was noted in 11 of 12 patients who were injected with 111In conjugated 2A11. Because no dose-limiting clinical toxicity was observed, a mathematical model was used to define the recommended Phase II dose of 250 mg/m2. This trial established that repeated doses of monoclonal antibody 2A11 could be given safely to patients, and sustained levels could be achieved for a 4-week schedule. Further evaluation of the antitumor effects of 2A11 is warranted.
Animals↗
Evaluation of prostaglandin F2 alpha treatment in dairy cows at risk for low fertility after parturition.
OBJECTIVE: To evaluate the effect of 2 postpartum prostaglandin F2 alpha (PGF 2 alpha) treatment protocols on reproductive performance of dairy cows at risk for low fertility. In addition, various medical conditions in cows that are recognized as having adverse effects on fertility were evaluated as criteria for fertility treatment. DESIGN: Prospective study. ANIMALS: 291 cows with, and 271 cows without, risk factors for low fertility. PROCEDURE: Cows at risk for low fertility were randomly assigned to 2 treatment groups. Group-1 cows received 3 i.m. injections of PGF2 alpha at weekly intervals after parturition, and group-2 cows received 1 i.m. injection of PGF2 alpha 17 to 24 days after parturition. RESULTS: Compared with a single PGF2 alpha treatment 17 to 24 days after parturition, there was no added benefit of 3 treatments with PGF2 alpha 3 to 10, 10 to 17, and 17 to 24 days after parturition in cows at risk for low fertility. Cows without risk factors for low fertility had 20% higher pregnancy rates, compared with cows with risk factors for low fertility. Twinning had a negative effect on future fertility. CLINICAL IMPLICATIONS: Results of this study indicate that further consideration should be given to the timing and intervals of PGF2 alpha administration after parturition. Risk factors for low fertility, such as retained placenta, twins, and assisted calvings, are valid criteria to evaluate different treatment options to improve fertility in dairy cows.
Animals↗
Pharmacokinetics of an indium-labeled IgG monoclonal antibody over a prolonged period.
This study was directed toward determining the pharmacokinetic fate of an IgG2a monoclonal antibody (MoAb). The 96.5 anti-melanoma MoAb was labeled with indium-111 and indium-114m and administered to BALB/c mice. The mice receiving 111In MoAb were sacrificed at 4 and 72 h, while those receiving 114mIn 96.5 MoAb (50-day physical half-life) were sacrificed at 4 h and 3, 15, and 30 days. Multiple tissues were counted against a standard of the injectate and the data expressed as percent injected dose per organ and percent total dose excreted in the urine and feces. The 111In- and 114mIn-labeled MoAbs had nearly identical distribution through 72 h. Over the 30-day period 25% of the 114mIn label was excreted in the urine and 50% eliminated in the feces. All of the tissues studied showed a decrease in 114mIn in the 30-day period. We conclude that the metabolic products of indium-labeled MoAbs, the indium itself, or a combination of both are eliminated from the tissues over a period of several weeks and do not accumulate to a significant extent in any single site.
Animals↗
Non-covalent antibody-mediated drug delivery.
High background activity produces imaging problems when scanning with antibodies. The following work is directed towards reducing this background. The murine monoclonal antibody (MAb) CHA-255 selectively binds 111In-nitrobenzyl EDTA, a molecule referred to as a 'hapten'. Balb/c mice studies indicate that if the antibody is administered prior to the hapten, it predictably modifies the biodistribution and pharmacokinetics of the hapten. The pharmacokinetics for the hapten were proportional to antibody dose and inversely proportional to the time interval between injection of the antibody and the hapten. A hybrid MAb was produced by the enzymatic digestion of CHA-255 and ZCE-025, an anticarcinoembryonic antigen (CEA) MAb, followed by joining of the two via a thioether linkage. The result was a F(ab')2 with affinity for both CEA and the hapten. The pharmacokinetics of the hapten were again dependent upon the kinetics and distribution of the hybrid antibody. Data in tumour models are also presented for 111In-nitrobenzyl EDTA and 111In-thioureabenzyl EDTA (TUBE), a newer hapten. The data indicate that the antibody-hapten system is capable of targeting tumour quickly while normal tissue rapidly becomes depleted of radioactivity. We conclude that the hapten-antibody technique shows some advantages over directly labelled MAb as a targeting system.
Animals↗
Effects of a prostaglandin F2 alpha synchronization program in lactating dairy cattle.
A comparison was made between two different methods of reproductive management in the dairy cow. One protocol administered prostaglandin to open cows weekly; the other administered prostaglandin to open cows with a corpus luteum identified by rectal palpation. Survival analysis was used to analyze the data. Cows receiving weekly doses of prostaglandin had a 30% higher pregnancy rate (number of pregnancies per time) than the cows receiving prostaglandin based on rectal palpation of a corpus luteum. The average number of days to first insemination was shorter in cows given prostaglandin weekly.
Animals↗
Albendazole in the treatment of onchocerciasis: double-blind clinical trial in Venezuela.
A double-blind clinical trial was conducted in Monagas State, Venezuela to assess the tolerance and efficacy of albendazole in the therapy of Onchocerca volvulus infection. Forty-nine patients (26 treated and 23 controls) received a 10-day course of albendazole (400 mg/day) or a placebo. Consistent with the excellent tolerance observed, albendazole did not kill microfilariae. However, analysis of changes in microfilarial densities (mf/mg of skin) over one year showed that albendazole was active against O. volvulus, presumably by interfering with embryogenesis. The nature, degree, and duration of this effect remain to be determined.
Adolescent↗
Preclinical evaluation of an anti-autocrine growth factor monoclonal antibody for treatment of patients with small-cell lung cancer.
We have evaluated an anti-autocrine growth factor monoclonal antibody for potential use in the treatment of patients with small-cell lung cancer. The monoclonal antibody, designated 2A11, binds to the C-terminal region of the autocrine growth factor gastrin-releasing peptide and neutralizes its growth-promoting effects in vitro and in vivo. Equilibrium-binding analysis demonstrated that the peptide binds to the antibody (dissociation constant = 1.5 x 10(-10) at least as avidly as it binds to the tumor peptide receptor. Pharmacokinetic studies in normal BALB/c mice demonstrated an initial clearance half-life (alpha t1/2) of 24.3 +/- 4 hours and a secondary clearance half-life (beta t1/2) of 1039.6 +/- 309 hours, and biodistribution studies revealed a distribution pattern which generally reflected blood flow. Single intravenous infusions of 2A11 (20 mg/20-25-kg dogs) into normal mongrel dogs with surgically created gastric fistulas antagonized the stimulatory effects of exogenously infused gastrin-releasing peptide or bombesin on plasma gastrin release and gastric acid secretion. Toxicology studies in normal dogs (with gastric fistulas) infused with 50 mg 2A11 intravenously three times a week for 4 weeks failed to reveal any adverse behavioral, clinical, or pathological effects. Four of six dogs developed an immune response to 2A11. Anti-idiotypic antibodies elicited in two cases did not mimic the functional effects of the peptide. We conclude that the concept of immunoblockade of an autocrine growth factor appears feasible in vivo.
Animals↗
A specific and potent immunotoxin composed of antibody ZME-018 and the plant toxin gelonin.
Murine monoclonal antibody ZME-018 recognizes a 240 Kda glycoprotein present on the surface of most human melanoma cells and on over 80% of human biopsy specimens tested. Gelonin is a ribosome-inactivating plant toxin similar in nature and rivaling the activity of ricin A chain. ZME-018 was coupled to purified gelonin using the reagents SPDP and 2-iminothiolane. The ZME-gelonin conjugate was purified by S-300 Sephacryl and Blue Sepharose chromatography, removing unreacted gelonin and antibody, respectively. PAGE analysis showed that ZME was coupled to 1, 2, or 3 gelonin molecules. The ZME-gelonin conjugate was 10(6)-fold more active than gelonin itself in inhibiting the growth of log-phase human melanoma cells in culture. The immunoconjugate was not cytotoxic to antigen negative T-24 (human bladder carcinoma) cells. Treatment of melanoma cells with recombinant IFN-alpha or TNF substantially augmented the cytotoxicity of the immunoconjugate while treatment with IFN-gamma had a minor effect. Using the human tumor colony assay of melanoma cells obtained from fresh biopsy specimens, greater than 90% growth suppression was observed in 2 of 4 samples tested at a concentration of 250 ng/ml. In addition, 25% growth suppression was observed with a third sample tested, and no growth suppression was observed in 1 sample. Thus, clonogenic melanoma cells are sensitive in vitro to the cytotoxic activity of this immunotoxin at concentrations which we presume are pharmacologically relevant.
Antibodies, Neoplasm↗
Antibody-mediated delivery of tumor necrosis factor (TNF-alpha): improvement of cytotoxicity and reduction of cellular resistance.
Recombinant human tumor necrosis factor-alpha (TNF-alpha) is a macrophage-derived, non-glycosylated (17 kDa) peptide that has a remarkably broad range of biological and immunological effects including antiviral action and cytotoxic and cytostatic effects. TNF-alpha was coupled to murine antibody ZME-018, which recognizes a 240 kDa glycoprotein present on over 80% of melanoma cells. The crosslinking was accomplished using the heterobifunctional crosslinking reagent, N-succimindyl 3-(2-pyridyldithio)proprionate (SPDP). After purification on gel-permeation and affinity columns, the resulting eluate was analyzed by non-reducing SDS-PAGE, which confirmed that the product was a mixture of ZME-018 coupled to one or two TNF-alpha molecules. The ZME-TNF conjugate was titered against murine L-929 cells to demonstrate the presence of active TNF. ELISA of the conjugate against target BRO human melanoma cells or non-target T-24 cells demonstrated specific binding only to target cells. Melanoma BRO cells were killed by the immunoconjugate (IC50 of 10 units/mL), whereas native TNF-alpha had no effect at concentrations greater than 50,000 units/mL. The immunoconjugate and TNF-alpha were inactive against T-24 non-target cells. These studies suggest that the sensitivity of cells to TNF was dramatically augmented by specific antibody mediated delivery to tumor cells.
Animals↗
Reduction of immunogenicity by covalent modification of murine and rabbit immunoglobulins with oxidized dextrans of low molecular weight.
This communication describes the covalent modification of monoclonal and polyclonal antibodies with oxidized dextrans of low molecular weight to generate conjugates having low immunogenicity in vivo. Conjugation conditions were optimized to generate monomeric, dextran-modified antibodies, free of both high-molecular-weight polymeric aggregates and unmodified antibodies. Conjugates could be prepared with varying levels of dextran substitution. These conjugates retained optimal immunoreactivity as well as in vivo pharmacokinetics and tumor-localization properties. In addition, multiple i.v. administrations of dextran-modified antibodies in animals did not elicit a measurable immune response to either the antibody or the dextran portion of these conjugates.
Animals↗
Scintigraphy with In-111-labeled monoclonal antitumor antibodies: kinetics, biodistribution, and tumor detection.
The purpose of this study was to evaluate and compare the kinetics, biodistribution, and tumor-depicting properties of three intact indium-111-labeled murine monoclonal antibodies (MoAb) and to determine if use of In-111-labeled F(ab')2 fragments of one of them had advantages over its intact counterpart for immunoscintigraphy. Ten patients with prostate cancer were studied with an anti-prostatic acid phosphatase MoAb (PAY-276), with a resultant tumor detection rate of 15%. Twenty-eight patients with melanoma were studied with ZME-018, a MoAb that targets the KD-240 melanoma antigen. Forty-three percent of the known lesions were detected. Forty patients with carcinoembryonic antigen (CEA)-producing tumors were studied, 24 with intact ZCE-025, and anti-CEA MoAb, and 16 with its F(ab')2 fragment. With use of intact ZCE-025, 34% of known lesions were detected versus 83% with its F(ab')2 fragment. The distribution of each MoAb appears unique unto itself with regard to kinetics, normal tissue distribution, and response to MoAb mass.
Antibodies, Monoclonal↗
Production responses of lactating dairy cows and heifers given thiabendazole at parturition.
A field trial was conducted to examine the effects on productivity of dairy cattle in 6 herds given thiabendazole at parturition. Criteria examined were milk and fat production, calving interval, services per conception, culling rate, and (in a subset of cows) hematologic response. Analysis of the data for all cows as a group did not indicate a significant effect. For first-calf heifers in 1 herd, a significant (P less than 0.01) and economically important increase in milk production was observed; why the effect was seen was not determined.
Animals↗
The hybridoma-an immunochemical laser.
The advent of hybridoma technology has provided the immunotechnologist a finely tunable instrument that should permit a marked advance in the immunologic sciences. The ability to choose the precise antibody required and the virtually unlimited availability of easily purified antibodies have already resulted in the simultaneous immunometric assay and potential reagents for immunoscintigraphy and immunotherapy. Using an antibody with a specific affinity and recognition for a specific antigenc determinant can greatly influence the shape and range of a radioimmunometric calibration curve. With monoclonal antibodies, assay systems based on immune complexes (e.g., turbidimetric assays and counterimmunoelectrophoresis) can be made more precise, thus permitting study of the basic physicochemical principles underlying the antigen-antibody reaction and the development of greatly improved quantitative assays. On the other hand, the ability to select an antibody exhibiting specific characteristics implies the necessity to select. One no longer has the luxury of using a mixture of antibodies, hoping to take advantage of the fact that some will have desirable secondary characteristics such as electrophoretic mobility or the ability to absorb to plastics.
Animals↗