Effects of cytosine arabinoside on human leukemia cells

Cytosine arabinoside (Ara-C) is used to treat leukemias, with complete remission induced by combination chemotherapy in approximately 70% of cases of acute myelogenous leukemia (AML). Ara-CTP acts as a competitive inhibitor of DNA polymerase and may also be incorporated into DNA. Accumulation of deoxyribonucleoside triphosphates (dNTPs) induced by Ara-C may indicate disruption of DNA synthesis in susceptible leukemia cells. A procedure has been developed for the quantification of Ara-CTP and dNTPs from small samples of leukaemia cells from patients (4 x 10(7) cells) activated with concanavalin A (10 micrograms/ml, 48 hr) and grown in the presence of [32P]orthophosphate (1.1 microM, 9 x 10(6) Ci/mol, 16 hr). The susceptibilities to Ara-C of the human leukemia cell lines CCRF-CEM (IC50 = 6.30 nM), CCRF-HSB-2 (IC50 = 10.4 nM) and MOLT-4 (IC50 = 10.0 nM) may be correlated with their abilities to accumulate high concentrations of Ara-CTP (> 1000 amol/cell) with increases of between 1.3- and 3.4-fold in dATP, dGTP and dTTP for the four cell lines, while dCTP decreased between 0.23- and 0.78-fold. By contrast, an Ara-C-resistant derivative of HL-60 cells (IC50 = 400 nM) accumulated only low concentrations of Ara-CTP (71 amol/cell) without significant changes in dNTPs. High concentrations of Ara-CTP in leukemia cells induce accumulations of dATP, dGTP and dTTP due to inhibition of DNA synthesis, and depletion of dCTP. This imbalance in the pools of the four dNTPs could lead to genetic miscoding and cell death.     

Results of a policy of primary repair of truncus arteriosus in the neonate

Although the early mortality for repair of truncus arteriosus has decreased in the modern era, routine correction in the neonate has not been widely adopted. To assess the results of our protocol of early repair, we reviewed 46 neonates and infants undergoing repair of truncus arteriosus at the University of Michigan Medical Center from January 1986 to January 1992. Their ages ranged from 1 day to 7 months (median 13 days) and weights from 1.8 kg to 5.4 kg (mean 3.1 kg). Repair was performed beyond the first month of life in only 8 patients, because of late referral in 7 and severe noncardiac problems in 1. Associated cardiac anomalies were frequently encountered, the most common being interrupted aortic arch (n = 5), nonconfluent pulmonary arteries (n = 4), hypoplastic pulmonary arteries (n = 4), and major coronary artery anomalies (n = 3). Truncal valve replacement was performed in 5 patients with severe regurgitation, 3 of whom also had truncal valve systolic pressure gradients of 30 mm Hg or more. The truncal valve was replaced with a mechanical prosthesis in 2 patients and with a cryopreserved homograft in 3 patients. Right ventricle-pulmonary artery continuity was established with a homograft in 41 patients (range 8 mm to 15 mm), a valved heterograft conduit in 4 (range 12 mm to 14 mm), and a nonvalved polytetrafluoroethylene tube in the remaining patient (8 mm). There were 5 hospital deaths (11%, 70% confidence limits 7% to 17%). Multivariate and univariate analyses failed to demonstrate a relationship between hospital mortality and age, weight, or associated cardiac anomalies. Only 1 death occurred among 9 patients with interrupted aortic arch or nonconfluent pulmonary arteries. Hospital survivors were followed-up from 3 months to 6.3 years (mean 3 +/- 0.4 years). Late noncardiac deaths occurred in 3 patients, all within 4 months after the operation. Actuarial survival was 81% +/- 6% at 90 days and beyond. Despite the prevalence of major associated conditions, early repair has resulted in excellent survival. We continue to recommend repair promptly after presentation, optimally within the first month of life.     

Constitutive activity of a chimeric D2/D1 dopamine receptor

Chimeric D1/D2 receptors were constructed to identify structural determinants of drug affinity and efficacy. We previously reported that chimeras that had D1 receptor transmembrane domain VII together with amino-terminal sequence from the D2 receptor were nonfunctional. D2/D1 chimeras were constructed that contained D2 receptor sequence at the amino- and carboxyl-terminal ends and D1 receptor sequence in the intervening region. Chimeric receptors with D2 sequence from transmembrane domain 7 to the carboxyl terminus together with D2 receptor sequence from the amino terminus through transmembrane helix 4 (D2[1-4,7]) and 5 (D2[1-5,7]) bound [3H]spiperone with high affinity, consistent with the hypothesis that D2 receptor transmembrane domain I or II is incompatible with D1 receptor transmembrane domain VII. D2[1-4,7] and D2[1-5,7] had affinities similar to D1 and D2 receptors for most nonselective dopamine antagonists and had affinities for most of the selective antagonists that were intermediate between those of the parent receptors. D2[1-4,7] and D2[1-5,7] mediated dopamine receptor agonist-induced stimulation and inhibition, respectively, of cAMP accumulation. The more efficient coupling of D2[1-5,7] to inhibition of cAMP accumulation, compared with the coupling of D2[5-7] and D2[3-7], supports the view that multiple D2 receptor cytoplasmic domains acting in concert are necessary for receptor activation of Gi. In contrast, D2[1-4,7], which contains only one cytoplasmic loop (the third) from the D1 receptor, is capable of activating Gs. D2[1-4,7] exhibited several characteristics of a constitutively active receptor, including enhanced basal (unliganded) stimulation of cAMP accumulation, high affinity for agonists even in the presence of GTP, and blunted agonist-stimulated cAMP accumulation. A number of dopamine receptor antagonists were inverse agonists at D2[1-4,7], inhibiting basal cAMP accumulation. Some of these drugs were also inverse agonists at the D1 receptor. Interestingly, several antagonists also potentiated forskolin-stimulated cAMP accumulation via D2[1-5,7] and via the D2 receptor, which could reflect inverse agonist inhibition of native constitutive activity of this receptor.     

Anterior choroidal artery aneurysm and stroke

We report the unique combination of a mid anterior choroidal artery (AChA) aneurysm and ischemic stroke presenting as a movement disorder in a young man. The mechanism for stroke in the AChA territory may either reflect a cause or an effect of aneurysm formation. We provide evidence for both arguments and speculate on the anatomic basis for the initial presentation of hemibody spasm.     

Granulocyte colony-stimulating factor (G-CSF) dose-dependent efficacy in peripheral blood stem cell mobilization in patients who had failed initial mobilization with chemotherapy and G-CSF

For 10 consecutive patients in our unit who did not show a significant rise in blood progenitor cells within 14 days following chemotherapy and G-CSF, we increased the G-CSF dose from 5 to 10 microg/kg/day (n = 9) or from 10 to 15 microg/kg/day (n = 1). As a result, there were significant increases in total yield as well as yield per apheresis of mononuclear cells, CD34+ cells and CFU-GM (P < 0.025, <0.01 and <0.005, respectively). After G-CSF dose escalation, six of the 10 patients had sufficient CD34+ cells for performing transplantation. These results demonstrate a dose-dependent response of progenitor cell mobilization by G-CSF when used in combination with chemotherapy. Moreover, increasing the dose of G-CSF as late as the third week of mobilization may still provide sufficient cell yield even with patients who did not show a significant mobilization with conventional doses of G-CSF.     

Postoperative allergic complications: the role of the anesthetist in conducting the immuno-allergic investigation

When peri-anaesthesia anaphylactic and/or anaphylactoid reactions occur, anaesthetist is the first investigator: the quality of immuno-allergological investigations depends on these initial investigational procedures. We have used sample kits for several years in order to make easier the immediate investigation. From retrospective analysis of the allergic complications which happened in 1997, the importance of these sample kits as well as the anaesthetist's part in the immuno-allergological management are examined. Nine observations were itemized (0.047%): 3 generalized erythema observations (grade I), in which atracurium was incriminated twice, and propacetamol once; 2 observations of grade II, in which vecuronium (elevated tryptase) and atracurium were incriminated; 4 anaphylactic shocks, in which three neuromuscular blocking drugs (suxamethonium, vecuronium and pancuronium), and one antibiotic (cloxacilline) were incriminated. The use of sample kits allowed an early diagnosis approach, confirmed by skin tests. Diagnosis should be thought closely between anaesthetists and immunologists for investigations.     

Comparison of gadolinium chelates with manganese-DPDP for liver lesion detection and characterization: preliminary results

Nonspecific extracellular gadolinium chelate (NEGd) was prospectively compared with managanese (Mn)-DPDP (Mn) for the detection and characterization of focal liver lesions of various histology. Seventeen patients with known or suspected focal liver lesions underwent NEGd and Mn-enhanced studies at 1.5 T. Study findings were correlated with histology (five patients), computed tomography (CT) examinations (17 patients), and 4- to 13-month imaging follow-up by CT and/or MR (five patients). NEGd studies were performed as serial postcontrast spoiled gradient echo (SGE) sequences, and Mn studies were performed as SGE sequences 15 and 30 min postocontrast and T1-weighted, fat-suppressed spin echo at 16 min. NEGd and Mn images were prospectively interpreted in a separate blinded fashion. Lesion detection and characterization were determined. NEGd and Mn-enhanced images demonstrated 61 and 49 lesions, respectively (p = .1, NS). A total of 60 and 33 lesions were characterized on NEGd and Mn images, respectively, which was significantly different (p = .008). No differences were observed for the detection and characterization of liver metastases; whereas there was a trend for superior detection and characterization for hepatocellular carcinoma with NEGA.     

Complex behaviours of AB model describing idiotypic network

A simple chemical model of the idiotypic network of immune systems, namely the AB model, has been developed by De Boer et al. The complexity of the system, such as the steady states, periodic oscillations and chaotic motions, has been examined by the authors mentioned above. In the present paper, the periodic motions and chaotic behaviours exhibited by the system are intuitively described. To clarify in which parameter domains concerned the system exhibits periodic oscillations and in which parameter domains the system demonstrates chaotic behaviours the Lyapounov exponent is explored. To characterize the strangeness of the attractors, the fractal dimension problem is worked out.