Autoimmunity caused by disruption of central T cell tolerance. A murine model of drug-induced lupus

A side effect of therapy with procainamide and numerous other medications is a lupus-like syndrome characterized by autoantibodies directed against denatured DNA and the (H2A-H2B)-DNA subunit of chromatin. We tested the possibility that an effect of lupus-inducing drugs on central T cell tolerance underlies these phenomena. Two intrathymic injections of procainamide-hydroxylamine (PAHA), a reactive metabolite of procainamide, resulted in prompt production of IgM antidenatured DNA antibodies in C57BL/6xDBA/2 F1 mice. Subsequently, IgG antichromatin antibodies began to appear in the serum 3 wk after the second injection and were sustained for several months. Specificity, inhibition and blocking studies demonstrated that the PAHA-induced antibodies showed remarkable specificity to the (H2A-H2B)-DNA complex. No evidence for polyclonal B cell activation could be detected based on enumeration of Ig-secreting B cells and serum Ig levels, suggesting that a clonally restricted autoimmune response was induced by intrathymic PAHA. The IgG isotype of the antichromatin antibodies indicated involvement of T cell help, and proliferative responses of splenocytes to oligonucleosomes increased up to 100-fold. As little as 5 microM PAHA led to a 10-fold T cell proliferative response to chromatin in short term organ culture of neonatal thymi. We suggest that PAHA interferes with self-tolerance mechanisms accompanying T cell maturation in the thymus, resulting in the emergence of chromatin-reactive T cells followed by humoral autoimmunity.     

Cure of malignant ascites and generation of protective immunity by monoclonal antibody-targeted activation of a glucuronide prodrug in rats

We examined the in vivo efficacy of targeting beta-glucuronidase (betaG) to activate a glucuronide prodrug (BHAMG) of p-hydroxyaniline mustard (pHAM) at hepatoma ascites in Sprague-Dawley rats. Injection i.p. of 500 microg RH1-betaG, a conjugate formed between recombinant betaG and monoclonal antibody RH1 with specificity for an antigen expressed on AS-30D rat hepatoma cells, into rats bearing AS-30D ascites resulted in the accumulation of 54 microg conjugate per 10(9) tumor cells after 2 hr. Ascites fluid and serum contained 0.53 and 0 microg/ml, respectively, RH1-betaG 2 hr after injection of the conjugate. Conjugate binding to AS-30D cells was heterogeneous and non-saturated, as determined by flow cytometry. BHAMG was less toxic than pHAM to SD rats based on measures of animal mortality, weight loss and hematological toxicity. Treatment of rats bearing established hepatoma ascites with 500 microg RH1-betaG followed 2 hr later with a single i.p. injection of 30 mg/kg BHAMG or 3 i.p. injections of 10 mg/kg BHAMG 2, 3 and 4 hr later resulted in the cure of 6/8 and 8/8 animals, respectively. Treatment with BHAMG or pHAM alone did not produce cures, whereas treatment with a control antibody-betaG conjugate and BHAMG produced significantly greater hematological toxicity compared to treatment with RH1-betaG and BHAMG. All cured rats were completely protected from rechallenge with 2 x 10(7) AS-30D cells, indicating that successful treatment of animals induced protective immunity.     

Partial congenital defect of the left pericardium: angiographic diagnosis and treatment by thoracoscopic pericardiectomy: case report

Twenty-six patients with an intracardiac myxoma underwent surgical resection at our institution from 1977 through 1992. Left atrial myxoma was diagnosed in 22 patients, left ventricular in 1, right atrial in 2, and right ventricular in 1. Six patients were asymptomatic; preoperative symptoms included dyspnea, arrhythmias, embolic episodes, and syncope. The diagnosis was established with transthoracic echocardiography in all cases but one. Surgery was performed in all cases with the aid of cardiopulmonary bypass with moderate hypothermia and cold crystalloid cardioplegia. One patient with a left ventricular myxoma died in a comatose state during the immediate postoperative period. Long-term clinical and echocardiographic evaluation was performed in 19 patients; results were excellent (all the patients were in New York Heart Association functional class I or II), and no recurrences were documented. The clinical characteristics, diagnostic methods, and surgical approach are presented and discussed.     

The greening of materials science and engineering

The field of materials science and engineering is advancing at a revolutionary pace. It is now generally recognized as being among the key emerging technological fields propelling our world societies into the twenty-first century. The driving forces for this revolutionary pace are at once social, economic, political, and technological. For example, relatively recent changes in United States federal policies in environmental control, hazardous waste management, and energy conservation along with heightened international trade competition have resulted in major changes in material processing and use patterns. These changing patterns are creating new requirements for material developments, substitutions, and associated processes. This paper traces the emergence of materials policy and technological developments through four sub-periods of history: the birth and development of engineering in the United States (1825–1900), the evolution of a national research infrastructure (1900–1945), the evolution of a national science policy (1945–1973), and the intensification of global interdependency (1973-present). Future trends in materials developments and future policy requirements are outlined. Technical Resources, of TRW, Inc., began his professional career in 1954 as a research metallurgist and reactor project engineer with General Electric Co. at the Hanford Atomic Products Operation in Richland, WA. In 1965 he joined Battelle Memorial Institute as a manager of the metallurgy research department and three years later became manager of the fuels and materials department. In 1970 Dr. Bement joined the faculty of Massachusetts Institute of Technology as professor of nuclear materials. From 1974 to 1976 he served as a member of the U.S.-U.S.S.R. Bilateral Exchange Program in Magnetohydrodynamics and was the organizer and principal investigator of the M.I.T. Fusion Technology Program. In 1976 Dr. Bement became Director of the Materials Sciences Office of the Defense Advanced Research Projects Agency and in 1979 was appointed Deputy Under-Secretary of Defense for Research and Engineering. Dr. Bement has co-authored one book, edited three books, and authored over 90 articles on materials science, energy, and defense technology. He is a Fellow of the American Nuclear Society, the American Society for Metals, and the American Institute of Chemists. In addition, he is a member of the American Institute for Mining, Metallurgical and Petroleum Engineers, and the American Society for Testing and Materials. He has received outstanding achievement awards from the Colorado Engineering Council in 1954, the Defense Advanced Research Projects Agency in 1977, and the Colorado School of Mines in 1984. In 1980 he was awarded the Distinguished Civilian Service Medal by the Secretary of Defense. He is a member of the National Academy of Engineering. Dr. Bement is chairman of the National Materials Advisory Board and a member of the Board of Army Science and Technology, the Board on Engineering Sciences, the Board on Assessment of National Bureau of Standards Programs, and the Board on Science and Technology for International Development of the National Research Council. Dr. Bement received an Engineer of Metallurgy (E. Met.) degree in 1954 from the Colorado School of Mines. He received an M.S. in Metallurgical Engineering from the University of Idaho in 1959, and a Ph.D. from the University of Michigan in 1963. He is a Lt. Colonel (ret.) in the U.S. Army Corps of Engineers. Dr. Bement and his family reside in Mayfield Village, OH.     

B7 blockade prevents activation-induced cell death of thymocytes

Although both B7 and its counter-receptor CD28 are expressed in the thymus, the role of B7 in thymic selection is not clear. We investigated the role of B7 in intrathymic deletion of antigen-specific T cells using a TCR transgenic model specific for antigen ovalbumin (OVA) and H-2Ad. Intraperitoneal injection of OVA induced apoptosis of thymocytes and drastic reduction of thymocyte numbers. This was significantly inhibited by co-injection of CTLA-4-Ig which blocks B7 co-stimulation. Deletion of T cells in the thymus following i.p. injection of OVA was associated with T cell pre-activation as demonstrated by T cell proliferation and cytokine production. Injection of CTLA-4-Ig blocked all these activation events and rescued thymocytes from activation-induced cell death. These results demonstrate that B7 is required for the activation-induced cell death of MHC class II-restricted thymocytes in vivo.     

Synthesis, absolute configuration, and analysis of malathion, malaoxon, and isomalathion enantiomers

Syntheses of the enantiomers of malathion, malaoxon, and isomalathion are reported herein. Malathion enantiomers were prepared from (R)- or (S)-malic acid in three steps. Enantiomers of malathion were converted to the corresponding enantiomers of malaoxon in 52% yield by oxidation with monoperoxyphthalic acid, magnesium salt. The four isomalathion stereoisomers were prepared via two independent pathways using strychnine to resolve the asymmetric phosphorus moiety. The absolute configurations of the four stereoisomers of isomalathion were determined by X-ray crystallographic analysis of an alkaloid salt precursor. A high-performance liquid chromatography technique was developed to resolve the four stereoisomers of isomalathion, and to determine their stereoisomeric ratios.     

Asbestos-related pericardial thickening detected by magnetic resonance imaging

Magnetic resonance imaging was performed in four male asbestos workers in whom the chest radiograph revealed pleural but not pulmonary or pericardial disease. Patients underwent thoracic multislice spin echo imaging, with measurement of left and right ventricular volumes at end-diastole and end-systole, and a study of the flow in the superior vena cava as an indirect measure to the filling of the right ventricle. Patients also underwent respiratory function tests and high-resolution computed tomography (HRCT). Magnetic resonance, but not HRCT, showed pericardial thickening in two patients. Magnetic resonance demonstrated reduced diastolic flow in the superior vena cava in one patient, reflecting impaired right ventricular filling. All other magnetic resonance measurements of cardiac function were normal. HRCT demonstrated mild asbestosis in three patients in which neither the chest radiograph nor magnetic resonance showed signs of parenchymal disease, and pericardiac calcification without thickening in one patient. It is concluded that magnetic resonance is superior to HRCT in identifying pericardial thickening, but that HRCT is superior to magnetic resonance in identifying asbestos-related pleural and pulmonary disease.