Response of drug-sensitive and -resistant L1210 leukemias to high-dose chemotherapy

Alkylating agent-sensitive and -resistant L1210 leukemia cell lines were used to determine the tumor response to dose levels of drugs that exceeded conventional doses up to a factor of 10. Since those dose levels were lethal to the host mice, tumor response was based on the results of in vivo bioassays of spleen and/or tumor from drug-treated and control mice. When mice bearing about 10(8) drug-sensitive leukemic cells were treated with a single, conventional (approximately 10% lethal) dose of cis-diamminedichloroplatinum, L-phenylalanine mustard (melphalan), or 1,3-bis(2-chloroethyl)-1-nitrosourea, 10(1) to 10(4) tumor cells were recovered by bioassay. Treatment at doses that were 2 to 8 times the 10% lethal dose of either of those drugs resulted in no recoverable cells and survival of all bioassay recipient mice. Mice bearing advanced L1210 leukemia resistant to cis-diamminedichloroplatinum (L1210/DDPt), 1,3-bis-(2-chloroethyl)-1-nitrosourea (L1210/BCNU), cyclophosphamide (L1210/CPA), or melphalan(L1210/L-PAM) also were treated with a 10% lethal dose and greater doses of the drug to which the tumor line was resistant. Bioassay results indicated a direct correlation between dose intensity and tumor cell kill, the response being linear. Similarly, when mice with L1210/BCNU were treated with high doses of N-(2-chloroethyl)-N'-(2,6-dioxo-3-piperidinyl)-N-nitrosourea or 1,1',1'-phosphinothioylidynetrisaziridine (thioTEPA) and when mice with L1210/DDPt were treated with cyclophosphamide, an increasing, linear cell kill resulted throughout the high-dose range. Overall, these results indicate that resistance to these alkylating agents can be overcome by dose intensification and that the tumor response is linear in relation to increasing dose level.     

Mycetoma-like manifestations in invasive pulmonary aspergillosis

Invasive pulmonary aspergillosis is characterized by radiological signs allowing a correct diagnosis, including differentiation from pulmonary candidiasis, when they are associated with appropriate clinical symptoms (neutropenia and fever persisting despite broad-spectrum antibiotics). In particular the formation of a pulmonary mycetoma in a previously normal lung is one of these signs. Unlike a simple fungus ball (the saprophytic form of aspergillosis), the rounded density of invasive pulmonary aspergillosis consists of sequestrum of devitalized lung tissue owing to blood vessel invasion by Aspergillus hyphae. This morphologic phenomenon is demonstrated in the present case report and is discussed together with the other roentgenological signs of the invasive aspergillosis.     

The effect of valproic acid on 65Zn distribution in the pregnant rat

The effect of valproic acid on the distribution of gavaged 65Zn in maternal and embryonic tissue of Sprague-Dawley rats was examined 24 h after gavaging of the drug on d 13 of pregnancy. Valproic acid treatment resulted in a significantly higher retention of 65Zn in maternal liver and lower amounts in uterus, placenta and embryos than in controls. Compared to controls, gel chromatography of maternal liver from valproic acid-treated dams showed higher 65Zn counts associated with a protein peak of molecular weight of 6,500, the approximate molecular weight of the Zn-binding protein metallothionein. These results support the idea that the teratogenicity of valproic acid is in part due to an induction of embryonic Zn deficiency secondary to a drug-induced sequestering of Zn into maternal liver that results in a decrease in maternal plasma Zn and subsequent reduction in embryonic Zn uptake.     

Antimicrobial activity of polymers coated with iodine-complexed polyvinylpyrrolidone

Polymer-associated infection is a problem of increasing importance in modern medicine. In a new approach to prevent such infections we have modified polyvinylfluoride (TEDLAR) films by graft copolymerization with N-vinylpyrrolidone to which iodine can be complexed. Grafting reaction was performed by the preirradiation technique using an electron accelerator. Grafted films were then treated in Lugol's solution for at least 24 h. Release of free iodine from the films was determined either by titration or using the agar disc diffusion test, showing an iodine release for up to 4-5 days. The antimicrobial activity of the films was tested in bacterial adhesion measurements. Bacterial and fungal cells in the range of 10(3) to 10(6) cfu/cm2 polymer were found on control samples without iodine, whereas on iodine-complexed films no viable cells could be detected at least for 5 days or even longer. Thus, microbial adhesion and growth can be inhibited by iodine-containing polymers.     

Closed-Chest Cardiopulmonary Bypass and Cardioplegia: Basis for Less Invasive Cardiac Surgery

Background. We developed a method of closed-chest cardiopulmonary bypass to arrest and protect the heart with cardioplegic solution. This method was used in 54 dogs and the results were retrospectively analyzed.

Methods. Bypass cannulas were placed in the right femoral vessels. A balloon occlusion catheter was passed via the left femoral artery and positioned in the ascending aorta. A pulmonary artery vent was placed via the jugular vein. In 17 of the dogs retrograde cardioplegia was provided with a percutaneous coronary sinus catheter.

Results. Cardiopulmonary bypass time was 111 ± 27 minutes (mean ± standard deviation) and cardiac arrest time was 66 ± 21 minutes. Preoperative cardiac outputs were 2.9 ± 0.70 L/min and postoperative outputs were 2.9 ± 0.65 L/min (p = not significant). Twenty-one-French and 23F femoral arterial cannulas that allowed coaxial placement of the ascending aortic balloon catheter were tested in 3 male calves. Line pressures were higher, but not clinically limiting, with the balloon catheter placed coaxially.

Conclusions. Adequate cardiopulmonary bypass and cardioplegia can be achieved in the dog without opening the chest, facilitating less invasive cardiac operations. A human clinical trial is in progress.     

Disseminated strongyloidiasis in AIDS: uncommon but important

Disseminated Strongyloides stercoralis infection is a rare and severe but treatable complication of AIDS. We present a case where this infection was successfully treated and review the available literature. Cases may present many years after they have left an area endemic for Strongyloides infection, emphasizing the need for a full travel history. Symptoms are typically gastrointestinal and pulmonary, with infiltrates often seen on chest radiography. Diagnosis requires stool examination and biopsy of affected sites. Treatment with repeated courses of thiabendazole (25 mg/kg twice daily for 5 days) was successful in our case, but maintenance regimens have not yet been defined. The relative rarity of this complication of AIDS suggests that, where both infections are present, disseminated strongyloidiasis only arises either when HIV-induced immunodeficiency is profound or, possibly, when it is accompanied by impaired granulopoiesis.     

Monoclonal antibodies to restricted and cross-reactive idiotopes on monoclonal rheumatoid factors and their recognition of idiotope-positive cells

Four human monoclonal rheumatoid factors (MRF) were used to raise a panel of mouse monoclonal antibodies (mAb) which were selected in a solid-phase radioimmunoassay for binding to MRF but not normal IgM. Three mAb, each raised against a different MRF, bound to the majority of MRF and also to most polyclonal RF. Four other mAb bound selectively to the MRF against which they were raised and to no other MRF, and rarely to any polyclonal RF. Competition studies using cold and radiolabeled mAb further indicated that these mAb recognize distinct and different epitopes on MRF. RF activity of MRF was inhibited by 3 of the 4 mAb binding to a single MRF and 2 of the 3 mAb binding to multiple RF. It was thus concluded that of this panel of mAb 3 recognized cross-reactive idiotopes and the remainder demonstrated highly restricted idiotopes on MRF. These mAb identified MRF idiotopebearing cells in the peripheral blood of 3 of the MRF donors (and a further subject with type II essential cryoglobulinemia), with a frequency ranging from 0.3–10% of all mononuclear cells with the mAb to restricted idiotopes or 1.5–17% with mAb to cross-reactive idiotopes. These anti-idiotopic mAb should thus provide a highly specific means of identifying and monitoring MRF-producing cells in vivo.     

A sensitive non-radioactive assay for pyrimidine nucleoside phosphorylase using reversed-phase high performance liquid chromatography

A new sensitive assay for pyrimidine nucleoside phosphorylase using non-radioactive substrates is described. With the natural substrate uridine (UR) and the analog, 5'-deoxy-5-fluorouridine (5'dFUR) conditions have been optimized to measure the product formation with reversed-phase high-performance liquid chromatography. Using automated injection large series of samples may be analyzed. The assay for UR phosphorylase appeared to be comparable to existing methods with radiolabeled UR as substrate regarding sensitivity and linearity. The assay has been used to measure kinetic parameters for 5'dFUR and UR in two cell lines from intestinal origin.