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PubMed1980

Role of polyclonal cell activation in the initiation of immune complex-mediated pulmonary injury following antigen inhalation.

The lung, by virtue of its anatomic situation, provides environmental antigens with unique access to host lymphoid tissues. In order to better understand the biologic consequences of antigen inhalation, we developed in animal model in which soluble proteins are administered in aerosol form to rabbits. By labeling these proteins with fluorochrome dyes or radioactive isotopes, the uptake, distribution, and fate of such proteins can be demonstrated both morphologically and quantitatively. Prompt host-antibody responses can be demonstrated to inhaled antigen, but not to comparable amounts of ingested antigen. Repeated administrations of antigen aerosol to immune animals produced little injury; in contrast, administration of aerosols containing phytohemagglutinin or cancanavalin A (Con A), plant lectins which activate leucocytes in a polyclonal fashion, induced a diffuse interstitial pneumonitis. When immune animals inhaled antigen plus Con A, devastating pulmonary necrosis was induced, in association with localized deposits of immune complexes containing antigen, antibody and complement. Such necrotic injury healed by scarring within 4 weeks. The necrotizing injury could be prevented by either decomplementation with cobra venom factor, or through inhibition of leucocyte responsiveness to Con A by administration of cholera toxin, a cAMP agonist. These studies indicate that antigen inhalation may serve as an important means of establishing "natural" immunity to environmental agents, but also may lead to severe pulmonary injury and fibrosis where the agents inhaled act not only as antigens but as polyclonal leucocyte activators as well.

Aerosols↗
PubMed1997

Measurement of erythrocyte volumes in splenectomized horses and sham-operated horses at rest and during maximal exercise.

Erythrocyte volumes of thoroughbred horses were measured. The volumes of splenectomized horses and sham-operated horses 2 hr after injection of 50Cr-tagged erythrocytes (at rest) and during maximal exercise were measured using the non-radioactive isotope 50Cr. Because splenic erythrocytes are released into circulation during exercise, it was estimated that the erythrocyte volumes of the sham-operated horses during maximal exercise are larger than those of the horses at rest. However, the erythrocyte volumes of the sham-operated horses at rest were about equal to those during maximal exercise. In the splenectomized horses, furthermore, erythrocyte volumes at rest and those at exercise were nearly equal. From these results, blood stored in the equine spleen is gradually mixed with circulating blood, and it was clarified that the phenomenon was completed within 2 hr. Although it is basically impossible to measure the circulating erythrocyte volume at rest using the erythrocyte tagged method, we observed that it is possible to measure the total erythrocyte volume using the 50Cr method. Also, the plasma volumes of the splenectomized horses during maximal exercise were found to be slightly smaller than those at rest. On the other hand, in the sham-operated horses, the plasma was decreased by a large quantity after maximal exercise. Therefore, it was suggested that the spleen participates in the phenomenon involving the disappearance of plasma from circulation due to exercise.

Animals↗
PubMed2006

Neurotoxicity of depleted uranium: reasons for increased concern.

Depleted uranium (DU) is a byproduct of the enrichment process of uranium for its more radioactive isotopes to be used in nuclear energy. Because DU is pyrophoric and a dense metal with unique features when combined in alloys, it is used by the military in armor and ammunitions. There has been significant public concern regarding the use of DU by such armed forces, and it has been hypothesized to play a role in Gulf War syndrome. In light of experimental evidence from cell cultures, rats, and humans, there is justification for such concern. However, there are limited data on the neurotoxicity of DU. This review reports on uranium uses and its published health effects, with a major focus on in vitro and in vivo studies that escalate concerns that exposure to DU might be associated with neurotoxic health sequelae.

Humans↗
PubMed1985

Bilateral pheochromocytoma associated with papillary adenocarcinoma of the thyroid gland; report of an unusual case.

A 31-year old woman was admitted to our clinic complaining of high blood pressure, dizziness, constipation, mental irritability and weight loss. The physical examination revealed goiter in her neck. The plasma levels of norepinephrine and epinephrine were 3.45 and 0.76 ng/ml, respectively. Urinary excretion of norepinephrine was 1 mg and epinephrine was 32.2 micrograms/24-hours. The examination by radiography and radioactive isotope revealed a tumor in the left adrenal region and another in the left lower lobe of the thyroid. After the operations, pheochromocytoma and papillary adenocarcinoma of the thyroid gland were recognized pathologically. However, 17 months later, the recurrence of pheochromocytoma in the contralateral adrenal region was discovered and removed. Although the co-existence of bilateral pheochromocytoma and papillary adenocarcinoma of the thyroid gland is not one of multiple endocrine neoplasia, to the best of our knowledge, only 7 such cases have been reported in the published literature.

Adenocarcinoma, Papillary↗
PubMed2004

Monoclonal antibodies for brain tumour treatment.

Conventional treatment of brain tumours includes surgical, radiotherapeutic and chemotherapeutic modalities. Nonetheless, the outcome of patients with brain tumours, in particular glioblastoma, remains poor. Immunotherapy with armed or unarmed monoclonal antibodies targeting tumour-specific antigens has emerged in the last two decades as a novel potential adjuvant treatment for all types of neoplasia. Many challenges to its implementation as a safe and viable therapy for brain tumours still need to be addressed; nevertheless, results from ongoing Phase I/II clinical trials are encouraging, as disease stabilisation and patient survival prolongation have been observed. Advances in preclinical and clinical research indicate that treatment of brain tumours with monoclonal antibodies can be increasingly adjusted to the characteristics of the targeted tumour and its environment. This aspect relies on the careful selection of the target antigen and corresponding specific monoclonal antibody, and antibody format (size, class, affinity), conjugation to the appropriate toxin or radioactive isotope (half-life, range), and proper compartmental administration.

Animals↗
PubMed2005

Monoclonal antibody therapy of leukaemias and lymphomas.

Paul Erhlich conceived of antibody-based immunotherapy in the nineteenth century. Rituximab, which is a chimeric monoclonal antibody produced by recombinant technology, became the first monoclonal antibody to be approved for haematological malignancies by the US Food and Drug Administration. Subsequently, radiolabelling technologies have made it possible to chelate radioactive isotopes to monoclonal antibodies, which retain their specificity and take advantage of targeted delivery of localised radiation. Radioimmunoconjugates are an attractive therapeutic option for lymphomas due to the inherent sensitivity to radiotherapy, the fact that the local emission of ionising radiation by radiolabelled antibodies may kill cells with or without the target antigen in close proximity to the bound antibody, and penetrating radiation may obviate the problem of limited antibody penetration into bulky, poorly vascularised tumours. This paper reviews rituximab, alemtuzumab and gemtuzumab ozogamicin as monoclonal antibody therapies for leukaemias and lymphomas.

Alemtuzumab↗
PubMed1975

Immunocytological methods for the identification and localization of antigens.

Immunocytologic techniques allow the study of antigenic cellular constituents by optical or electron microscopy, Antibodies labelled with tracers such as fluorochromes, enzymes, radioactive isotopes, or large electron-dense molecules form the basis of these techniques. The immunochemical procedures involved in the preparation of such conjugates are well defined. Satisfactory results, however, also depend upon the proper preparation and processing of the tissue or cell suspension being studied.

Animals↗
PubMed2006

Review of clinical radioimmunotherapy.

Radioimmunotherapy involves a form of biologically targeted radiopharmaceutical treatment in which a radioactive isotope (typically a short-range, high-energy beta-emitter) is chemically bound to a target-specific monoclonal antibody or fragment. Thus, these radioimmunoconjugates combine the exquisite targeting specificity of the humoral immune system with the known cancer-killing power of high-energy radiotherapy. To date, two radioimmunotherapy agents have been fully approved for commercial use: 90Yttrium ibritumomab tiuxetan and (131)Iodine tositumomab. Both compounds target the CD20 surface molecule found on normal and malignant B cells, and both are medically indicated for the treatment of indolent B-cell lymphoma and related conditions. Clinical results are excellent (20-40% complete response rates and 60-80% overall response rates) and toxicity is typically quite mild. Current research is now attempting to both explore the biology of these compounds and to expand the spectrum of CD20+ diseases that could be treated using either or both of these active agents. Concurrently, work is in progress to achieve the same excellent clinical results using antibodies specific for other, more common epithelial tumors. This work is at an earlier stage than the lymphoma work, partly due to the high innate radiosensitivity of the lymphoid system. Thus, various enhancement methodologies are being explored to increase clinical response rates for these solid tumors, and a number of solid tumor RIT agents are now in early-stage clinical trials. The most likely pattern of use for this field in the next 5 years will probably involve combination or sequential regimens incorporating both radioimmunotherapy and more conventional chemotherapy or external radiotherapy.

Antibodies, Monoclonal↗
PubMed2004

Stage-specific activity of potential antimalarial compounds measured in vitro by flow cytometry in comparison to optical microscopy and hypoxanthine uptake.

The evaluation of new antimalarial agents using older methods of monitoring sensitivity to antimalarial drugs are laborious and poorly suited to discriminate stage-specific activity. We used flow cytometry to study the effect of established antimalarial compounds, cysteine protease inhibitors, and a quinolone against asexual stages of Plasmodium falciparum. Cultured P. falciparum parasites were treated for 48 h with different drug concentrations and the parasitemia was determined by flow cytometry methods after DNA staining with propidium iodide. P. falciparum erythrocytic life cycle stages were readily distinguished by flow cytometry. Activities of established and new antimalarial compounds measured by flow cytometry were equivalent to results obtained with microscopy and metabolite uptake assays. The antimalarial activity of all compounds was higher against P. falciparum trophozoite stages. Advantages of flow cytometry analysis over traditional assays included higher throughput for data collection, insight into the stage-specificity of antimalarial activity avoiding use of radioactive isotopes.

Animals↗
PubMed2006

Normal organ radiation dosimetry and associated uncertainties in nuclear medicine, with emphasis on iodine-131.

In many medical applications involving the administration of iodine-131 ((131)I) in the form of iodide (I(-)), most of the dose is delivered to the thyroid gland. To reliably estimate the thyroid absorbed dose, the following data are required: the thyroid gland size (i.e. mass), the fractional uptake of (131)I by the thyroid, the spatial distribution of (131)I within the thyroid, and the length of time (131)I is retained in the thyroid before it is released back to blood, distributed in other organs and tissues, and excreted from the body. Estimation of absorbed dose to nonthyroid tissues likewise requires knowledge of the time course of activity in each organ. Such data are rarely available, however, and therefore dose calculations are generally based on reference models. The MIRD and ICRP have published metabolic models and have calculated absorbed doses per unit intake for many nuclides and radioactive pharmaceuticals. Given the activity taken into the body, one can use such models and make reasonable calculations for average organ doses. When normal retention and excretion pathways are altered, the baseline models need to be modified, and the resulting organ dose estimates are subject to larger errors. This paper describes the historical evolution of radioactive isotopes in medical diagnosis and therapy. We nonmathematically summarize the methods used in current practice to estimate absorbed dose and summarize some of the risk data that have emerged from medical studies of patients with special attention to dose and effects observed in those who received (131)I-iodide in diagnosis and/or therapy.

Body Burden↗
PubMed1996

Comparison of a radioactive and non-radioactive method for sequencing foot and mouth disease virus isolates.

The authors compare the radioactive method of detecting foot and mouth disease virus sequence products with a non-radioactive, silver stain sequencing method. The latter was found to compare favourably to the radioactive technique for detecting such products. The silver stain sequencing method was simple and did not require expensive specialised equipment. This new approach will be particularly useful in developing countries, since the method does not depend on the availability of fresh radioactive isotopes and is also safer and considerably cheaper.

Animals↗
PubMed1997

Decontamination of chicken carcasses artificially contaminated with Salmonella.

A study was conducted to evaluate the efficacy of three chemical disinfectants and of ionising radiation in reducing the level of contamination in chicken carcasses which had been artificially contaminated with Salmonella Virchow. Chicken carcasses were obtained from a local abattoir. Five carcasses and one control carcass were used to test each concentration of disinfectant and the radiation. The amount of contaminant employed was 0.5 ml of 10(4) colony-forming units per ml of S. Virchow spread over the thigh, breast and wing areas. All treatments were conducted in duplicate. The three disinfectants used were as follows: calcium hypochlorite, at concentrations of 20 ppm, 50 ppm, 100 ppm and 200 ppm of available chlorine. Lactic acid at concentrations of 0.5%, 0.75% and 1%. Hydrogen peroxide compound at concentrations of 1%, 2% and 3%. Five inoculated carcasses were immersed at a time in one disinfectant concentration for 15 min, while the control carcasses were simultaneously immersed in water free from disinfectants. Five carcasses, each in a plastic bag, were subjected to varying ascending doses (from 2 to 7 k gray [kGy]) of ionising radiation from radioactive isotopes of cobalt 60. A bacteriological examination of each carcass was conducted after the treatment to determine the presence or absence of S. Virchow. The number of carcasses which gave positive results showing the presence of Salmonella decreased after chemical treatment, but the organism was not completely eliminated. However, in those carcasses subjected to 7 kGy of radiation, Salmonella was eliminated and no changes in the appearance, colour or smell of the carcasses were observed.

Animals↗
PubMed2001

Imaging methods in gene therapy of cancer.

Clinical gene therapy needs non invasive tools to evaluate the efficiency of gene transfer. This includes the evaluation of infection efficiency as well as the verification of successful gene transfer in terms of gene transcription. These informations can be used for therapy planning, follow up studies in treated tumors and as an indicator of prognosis. Therapy planning is performed by the assessment of gene expression for example using radiolabeled specific substrates to determine the activity of suicide enzymes as the Herpes Simplex Virus thymidine kinase or cytosine deaminase. Furthermore, other in vivo reporter genes as receptors, antigens or transport proteins may be used in bicistronic vector systems for the evaluation of gene transduction and expression. This is done using radiolabeled ligands, antigens or substrates. Follow up studies with magnetic resonance imaging, single photon emission tomography or positron emission tomography may be done to evaluate early or late effects of gene therapy on tumor volume, metabolism or proliferation. Finally, enhancement of radioactive isotope accumulation in tumors by transfer of the appropriate genes may be used for the treatment of malignant tumors.

Animals↗
PubMed2004

Two-domain vascular disruptive agents in cancer therapy.

The two-domain vascular drug constructs are selective anti-cancer agents capable of specific targeting and subsequent elimination of endothelial cells lining tumor blood vessels. The destruction of existing vasculature within tumor tissue causes insufficient oxygenation of adjacent neoplastic cells and their necrotic death. The recognition (cognitive) domain of the vascular disruptive agents is responsible for recognizing markers specific for endothelial cells. This domain can be formed by variable regions of antibodies or by suitable ligands (such as those binding various integrin or growth factor receptors). The effector domain, in turn, can be constructed from proteins participating in blood clotting process, as well as from toxins, cytokines, radioactive isotopes or pro-apoptotic factors. This article outlines issues important for constructing such two-domain vascular disruptive agents and emphasizes the modularity of their assembly. Several pharmacokinetic and pharmacodynamic properties of these novel agents are discussed. Compared to known cytostatic substances exerting anti-angiogenic effects, such vascular disruptive agents can be much more effective as cytotoxic agents, especially in combination with proven anti-cancer drugs.

Angiogenesis Inhibitors↗
PubMed2006

Treatment of acute leukaemias with monoclonal antibodies: current status and future prospects.

Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to direct cellular effects, antibodies can carry substances to the targeted cells, such as radioactive isotopes, toxins, and antineoplastic agents. At present monoclonal antibodies, directed against both lymphoid antigens (CD 20 and CD 52) and a myeloid antigen (CD33) are available for clinical use. In ALL, rituximab, a humanized anti CD20 antibody, has been combined to chemotherapy mainly in mature B-ALL and Burkitt's lymphoma and preliminary results are promising. Alemtuzumab is an anti-CD52 humanized antibody, which showed anti-tumour activity in CLL; clinical effects were observed in some patients with relapsed adult ALL. Monoclonal antibodies against myeloid antigens have been prevalently used in acute myeloid leukaemias (AML), where the most utilised immunological target is CD33. The CD33 molecule is expressed by approximately 90% of AMLs but not on CD34(+) bone marrow-resident hematopoietic stem cells. The humanized anti-CD33 monoclonal antibody HuM195 has only modest activity against overt AML, but it can eliminate minimal residual disease. Radioimmunotherapy with beta-particle-emitting isotopes targeting CD33 shows a major efficacy. Targeted chemotherapy with the anti-CD33-calicheamicin construct gemtuzumab ozogamicin (GO) has produced remissions as a single agent in patients with relapsed AML and appears promising when used in combination with standard chemotherapy. GO is composed of a humanized immunoglobulin G(4) (IgG(4)) monoclonal antibody (mAb), targeting the CD33 antigen and linked to a calicheamicin derivative, a cytotoxic anthracycline antibiotic. GO has been approved by FDA as second-line therapy in older patients with AML. The most common adverse effects of monoclonal antibodies are myelosuppression, infusion-related reactions, and hypersensitivity reactions. Rituximab may cause tumour lysis syndrome. Alemtuzumab causes immunosuppression, increasing the risk of infection. GO may cause hepatotoxicity.

Acute Disease↗
PubMed2000

Plasmalemmal transport of magnesium in excitable cells.

In excitable cells, the concentration of intracellular free Mg2+ ([Mg2+]i) is several hundred times lower than expected if Mg2+ ions were at electrochemical equilibrium. Since Mg2+ is a permeant ion across the plasmalemma, it must be constantly extruded. An ATP-dependent Na/Mg exchanger has been proposed as the sole mechanism responsible for Mg2+ extrusion. However, this hypothesis fails to explain numerous observations including the fact that K+ and Cl- appear to be involved in Mg2+ transport. Until now three main limitations have hampered the studies of plasmalemmal Mg2+ transport: i) 28Mg, the only useful radioactive isotope of Mg2+, has a short half-life and is difficult to obtain; ii) squid giant axons, the ideal preparation to carry out transport studies under "zero-trans" conditions, are only available during the summer months; and iii) the ionic fluxes mediated by the Mg2+ transporter are very small and difficult to measure. The purpose of this manuscript is to review how these limitations have been recently overcame and to propose a novel hypothesis for the plasmalemmal Mg2+ transporter in squid axons and barnacle muscle cells. Overcoming the limitations for studying the plasmalemmal Mg2+ transporter has been possible as a result of the following findings: i) the Mg2+ exchanger can operate in "reverse", thus extracellular Mg2+-dependent ionic fluxes (e.g., Na+ efflux) can be utilized to measure its activity; ii) internally perfused, voltage-clamped barnacle muscle cells which are available all year long can be used in addition to squid axons; and iii) phosphoinositides (e.g., PIP2) produce an 8-fold increase in the ionic fluxes mediated by the Mg2+ exchanger. The hypothesis that we postulate is that, in squid giant axons and barnacle muscle cells, a 2Na+2K+2Cl:1Mg exchanger is responsible for transporting Mg2+ across the plasmalemma and for maintaining [Mg2+]i under steady-state conditions.

Animals↗
PubMed1998

Impact of radioimmunoscintigraphy on the management of colorectal and ovarian cancer patients: a retrospective study.

Noninvasive differentiation of benign from malignant disease has emerged as an important diagnostic challenge in the current age of health-care cost containment. Most physicians today acknowledge that early and accurate detection of cancer is important in successful treatment. Antibodies have been developed, labeled with radioactive isotopes, and used to detect and treat malignant tumors. During the past few years, several radiolabeled antibodies have received approval from the U.S. Food and Drug Administration for imaging colorectal, lung, ovarian, and prostate carcinomas, thus expanding and improving the physician's ability to detect and follow cancer in patients. At present, there is ample evidence in the literature to suggest that imaging with the 111In-labeled monoclonal antibody B72.3 is clinically useful for detecting primary/recurrent colorectal and recurrent ovarian carcinomas. In this article, we present a retrospective review of 136 patients from 10 moderate-sized hospitals who underwent a study with radioimmunoscintigraphy (RIS), using the 111In B72.3 antibody and standard diagnostic examinations for the detection of recurrent colorectal or ovarian carcinoma. The resulting data were analyzed in an effort to determine if (and how) information obtained from this radioimmunoscintigraphic procedure is being used by referring physicians. Our findings suggest a gradually increasing use of scan findings with the 111In B72.3 antibody in making patient-management decisions.

Antibodies, Monoclonal↗
PubMed2000

Novel cancer therapies: more efficacy, less toxicity and improved organ preservation.

Novel approaches to the treatment of cancer include techniques such as gene therapy, antiangiogenic therapy, monoclonal antibodies either alone or linked with radioactive isotopes or cytotoxins, cancer immunotherapy and vaccines, oligonucleotides and antisense technologies as well as anticancer drugs targeting single metabolic processes, enzymes or oncoproteins. However, substantial improvements are also being made in more conventional cancer treatment modalities. These comprise radiotherapy given concomitantly with chemotherapy, which appears to improve treatment results in a number of common types of human cancer. Other important advances include conformal and intensity-modulated radiation therapy, which may allow for higher target doses with little or no increase in toxicity. Stereotactic radiation therapy for extracranial targets is also being developed, as well as biologically targeted radiation therapy, in which targeting is based on metabolic pathways or carrier molecules, such as boronated compounds in boron neutron capture therapy or monoclonal antibodies in radioimmunotherapy. Sentinel node biopsy and neoadjuvant chemotherapy for breast cancer represent advances in surgery and cancer chemotherapy, which may also allow for a greater chance for organ and tissue preservation without a loss in treatment efficacy.

Breast Neoplasms↗