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.     

Teleconferencing: A Better Way to Meet

As most IS managers know, time is often wasted during most business meetings. As technological advances in the various types of teleconferencing systems continue, teleconferencing will serve as the preferred method of conducting meetings because of the resulting time and cost savings.     

CORPORATE NETWORK INFRASTRUCTURE Pulblic, Private, or Hybrid?

Designing a geographically extensive corporate network at the lowest cost means dealing with the vagaries of handling multiple carriers and widely varying levels of service. Further complicating matters are tariff structures that often dictate optimum corporate network infrastructures. This column reviews some of the available and emerging services and the best network structure options.     

H2S optimization for lignite liquefaction

Two lignite samples, Beulah No. 3 and Big Brown No. 1, were liquefied at 420 °C using H₂ and synthesis gas to determine the optimum beneficial amount of H₂S in the batch autoclave reactor. Under the conditions employed, 50–100 psi partial pressure of H₂S, nominally 4–10 wt% of daf lignite, was optimum for both samples. Synthesis gas outperformed H₂ with and without H₂S for the liquefaction of the two coals.     

Transmission electron microscopic analysis of kidney glomeruli obtained by fine-needle aspiration

Aspiration biopsy of tumors and transplanted organs is a popular atraumatic method for diagnosis and also for the management of patients. Apart from the cytological analyses, it is clear that large aggregates of cells are obtained and these may be examined by electron microscopy. A study was carried out with dogs to assess the yield of intact glomeruli and tubules, resulting from a standard fine-needle aspiration procedure. Employing a 20-gauge needle, yields of approximately ten intact glomeruli were obtained with a tissue processing protocol that utilized filtration through a nylon mesh and backwashing, to resuspend the trapped aggregates. Processing for electron microscopy was carried out in microcentrifuge tubes. The ultrastructural preservation was excellent and the extension of these studies to investigations of not only renal transplantation, but also for diagnosis in human renal diseases of a broad spectrum, is suggested.     

The experimental determination of the neutron cross section for selected solvents

An experiment was conducted in order to determine the macroscopic neutron cross section of various solvents useful in neutron radiographic inspection. These solvents are used to dissolve the salts of high cross-section elements in order to formulate a fluid of maximal neutron cross section. The resulting fluid could then be used as a contrast enhancing agent in neutron radiographic inspection. This experiment was planned using statistical experimental design techniques. The results of this experiment provided a quantitative measure of the mean and standard deviation of the macroscopic neutron cross section for the nine fluids investigated. A control fluid was found to be in close agreement with published values.