Excessive Aluminum Accumulation in the Bones of Patients on Long‐Term Parenteral Nutrition

Background: Aluminum (Al) contamination of parenteral nutrition (PN) solutions remains a concern for long‐term PN patients. Al accumulates particularly in bone. Excessive exposure to Al may result in increased Al body burden and impaired bone formation and mineralization, leading to bone disease. Although the U.S. Food and Drug Administration (FDA) has limited Al contamination in large‐volume parenteral solutions, small‐volume parenterals may still contribute considerable amounts of Al to PN solutions. The goal of this study is to determine whether or not long‐term adult PN patients remain at risk for increased bone Al accumulation. Methods: We measured Al accumulation in autopsy bones from 7 patients who had received PN for 2–21 years and compared bone Al levels with those in living control patients undergoing hip or knee replacement. Electrothermal atomic absorption spectrometry was used for bone Al measurements. Results: When compared with bone Al content in controls, markedly elevated Al levels (P < .0001) were found in the bones of all but 1 patient, who received PN for only 2 years before death. Even greater Al accumulation was found for PN patients who developed late renal impairment (P = .0159). Conclusions: We conclude that long‐term adult PN patients continue to be at risk for Al toxicity.     

Olsalazine in maintenance of clinical remission in patients with ulcerative colitis

Frequent minor side effects are associated with sulfasalazine. The realization that it is the 5-aminosalicylic acid moiety that is the active component of sulfasalazine and that the side effects are probably due to the sulfapyridine has prompted the search for a similar but safer compound. Olsalazine, consisting of two molecules of 5-ASA without sulfasalazine may avoid the problems due to sulfasalazine. One hundred one patients were entered into a double-blind placebo-controlled study of the use of olsalazine 92 g daily) in preventing relapse in patients who had recently recovered from an acute attack of ulcerative colitis. Patients were treated for 12 months. Forty-nine were randomized to olsalazine (39 with limited and 10 with extensive disease) and 52 to placebo (42 with limited and 10 with extensive disease). Life-table analysis showed that the median time to relapse in patients on olsalazine was 342 days, which was significantly longer than the 100 days in the placebo group (P=0.024). The most important side effect experienced with olsalazine that necessitated withdrawal from the study was drug-induced diarrhea in 16% (8/49). There was a similar incidence of minor side effects reported in the two groups, and in no patients were major or dangerous side effects reported. In patients who did not develop diarrhea, olsalazine was well tolerated and successfully prevented rapid relapse in the recently ill patients entered into this study.     

The genotype and phenotype of T cell and non-T, non-B acute lymphoblastic leukemia

We used Southern blot analysis to investigate the T cell receptor and immunoglobulin (Ig) genes in tumor DNA derived from 13 patients with acute lymphoblastic leukemia (ALL). Rearrangement of both alleles of the T cell receptor beta chain gene was demonstrated in the three individuals with T cell ALL, while the Ig genes remained in germline configuration. In contrast, in nine of ten patients with non-T, non-B ALL (seven common ALL antigen [CALLA]-positive), Ig genes were rearranged while the T cell receptor genes were intact: the noteworthy exception was a CALLA-positive individual in whom one allele of the T cell receptor was rearranged and in whom a minor rearranged Ig band was detected as well. This exception indicates that CALLA-positive non-T, non-B ALL includes proliferations that have undergone an initial genetic step toward T cell differentiation. With probes now available for both the Ig and T cell receptor genes, analysis of genomic tumor DNA is useful in all variants of ALL.     

The Role of Late INa and Antiarrhythmic Drugs in EAD Formation and Termination in Purkinje Fibers

Multiple components of cardiac Na current play a role in determining electrical excitation in the heart. Recently, the role of nonequilibrium components in controlling cardiac action potential plateau duration, and their importance in regulating the occurrence of afterdepolarizations and arrhythmias have garnered more attention. In particular, late Na current (late I _Na) has been shown to be important in LQT2 and LQT3 arrhythmias. Class III agents like dofetilide, clofilium, and sotalol, which can all cause a drug-induced form of LQT2, significantly lengthen action potential duration at 50% and 90% repolarization in isolated rabbit Purkinje fibers, and can initiate the formation of early afterdepolarizations, and extra beats. These actions can lead to the development of a serious ventricular tachycardia, torsades de pointes, in animal models and patients. However, pretreatment with agents that block late I _Na, like lidocaine, mexiletine, and RSD1235, a novel mixed ion channel blocker for the rapid pharmacologic conversion of atrial fibrillation, significantly attenuates the prolonging effects of Class III agents or those induced by ATX-II, a specific toxin that delays Na channel inactivation and amplifies late I _Na greatly, mimicking LQT3. The Na channel block caused by lidocaine and RSD1235 can be through the open or inactivated states of the channel, but both equivalently inhibit a late component of Na current ( I _Na), recorded at 22°C using whole-cell patch clamp of Nav1.5 expressed in HEK cells. These protective actions of lidocaine, mexiletine, and RSD1235 may result, at least in part, from their ability to inhibit late I _Na during action potential repolarization, and inhibition of the inward currents contributing to EAD and arrhythmia formation.     

Urinary 6 beta-hydroxycortisol excretion in rheumatoid arthritis

The objective was to analyse whether the activity of the cytochrome P450 isoenzyme CYP3A4 is altered by disease activity of rheumatoid arthritis (RA). Urinary 6 beta-hydroxycortisol excretion, expressed as a fraction of the urinary creatinine output, was measured in 21 patients with RA treated with three different disease-modifying anti- rheumatic drugs (DMARDs) over 24 weeks. There were no correlations between urinary 6 beta-hydroxycortisol/creatinine (6 beta-OHC/Creat) ratio and measurements of disease activity such as plasma viscosity, Ritchie articular index and early morning stiffness. In addition, the three DMARDs sulphasalazine, sodium aurothiomalate and D-penicillamine, smoking and the intake of various CYP3A4 substrates had no consistent detectable effect on the 6 beta-OHC/Creat ratio. There is no evidence that the dosage of drugs metabolized by the CYP3A4 isoenzyme needs to be adjusted for disease activity in RA.      

Effects of lipid A and liposomes containing lipid A on platelet and fibrinogen production in rabbits

The effect of the lipid A moiety of endotoxin on platelet and fibrinogen production was studied in rabbits. Lipid A was infused intravenously in doses ranging from 1 to 100 micrograms/kg body mass; 18 hr later, selenomethionine-75Se was injected intravenously and its incorporation into fibrinogen and platelets determined. Lipid A in saline stimulated fibrinogen and platelet production, but the dose required was 50--100 times that required for an intact endotoxin. Although lipid A solubilized in triethylamine (TEA) was at least 60 times more active in the Limulus amebocyte lysate assay than was lipid A suspended in saline, the sensitivity of platelet and fibrinogen production to solubilized lipid A was increased only twofold. Incorporation of lipid A into liposomes had no effect on its Limulus activity. Lipid A in liposomes continued to stimulate platelet, but not fibrinogen, production. Leukopenia that was induced by lipid A in TEA did not occur when rabbits received the same dose of lipid A in liposomes. Lipid A, like intact endotoxin, can stimulate platelet and fibrinogen production and induce leukopenia but the doses required are high. The low solubility of lipid A in aqueous solutions may be only one factor that determines its biologic activity.     

K562 human erythroleukemia cells demonstrate commitment

Commitment, ie, the decision to express a differentiated phenotype and to terminate proliferation irreversibly in the absence of inducer, was investigated in K562 human erythroleukemia cells. Cells were cultured for 0, 1, 2, 3, or 4 days with inducer and then plated in medium containing methylcellulose without inducer. Daily after plating, hemoglobin content was scored by benzidine staining, and growth was assessed by estimating the cell number per colony. With all inducers used, three types of colonies were found, those containing only benzidine-positive cells, those containing only benzidine-negative cells, and those containing both cell types (mixed colonies). Thymidine produced a progressive increase in the percentage of positive and mixed colonies and a progressive fall in the percentage of negative colonies. Whereas negative colonies grew at an exponential rate with a generation time of about 20 hours, positive colonies reached an average maximum size of 16 cells, representing a total of four divisions. Butyrate had a similar effect, except that the rise was greater for mixed colonies than for positive colonies, and the plateau in positive colony size was less evident. In contrast, CO2 depletion or hemin treatment induced an increase in the fraction of cells staining benzidine positive that was lost rapidly upon removal of the inducing condition. Thus, of the four conditions, thymidine and butyrate caused commitment, whereas hemin and CO2 depletion did not. Thus K562 cells, like Friend cells, demonstrate commitment, but, unlike Friend cells, demonstrate a significant rate of commitment in the absence of inducer and hence form a significant percentage of mixed colonies with or without inducer.