Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B

BACKGROUND: About 65 percent of previously untreated adults with primary acute myeloid leukemia (AML) enter complete remission when treated with cytarabine and an anthracycline. However, such responses are rarely durable when conventional postremission therapy is administered. Uncontrolled trials have suggested that intensive postremission therapy may prolong these complete remissions. METHODS: We treated 1088 adults with newly diagnosed AML with three days of daunorubicin and seven days of cytarabine and randomly assigned patients who had a complete remission to receive four courses of cytarabine at one of three doses: 100 mg per square meter of body-surface area per day for five days by continuous infusion, 400 mg per square meter per day for five days by continuous infusion, or 3 g per square meter in a 3-hour infusion every 12 hours (twice daily) on days 1, 3, and 5. All patients then received four courses of monthly maintenance treatment. RESULTS: Of the 693 patients who had a complete remission, 596 were randomly assigned to receive postremission cytarabine. After a median follow-up of 52 months, the disease-free survival rates in the three treatment groups were significantly different (P = 0.003). Relative to the 100-mg group, the hazard ratios were 0.67 for the 3-g group (95 percent confidence interval, 0.53 to 0.86) and 0.75 for the 400-mg group (95 percent confidence interval, 0.60 to 0.94). The probability of remaining in continuous complete remission after four years for patients 60 years of age or younger was 24 percent in the 100-mg group, 29 percent in the 400-mg group, and 44 percent in the 3-g group (P = 0.002). In contrast, for patients older than 60, the probability of remaining disease-free after four years was 16 percent or less in each of the three postremission cytarabine groups. CONCLUSIONS: These data support the concept of a dose-response effect for cytarabine in patients with AML who are 60 years of age or younger. The results with the high-dose schedule in this age group are comparable to those reported in similar patients who have undergone allogeneic bone marrow transplantation during a first remission.     

Modeling considerations in seismic assessment of RC bridges using state-of-practice structural analysis software tools

The increasing awareness of the general society toward the seismic safety of structures has led to more restrictive performance requirements hence, many times, to the need of using new and more accurate methods of analysis of structures. Among these, nonlinear static procedures are becoming, evermore, the preferred choice of the majority of design codes, as an alternative to complete nonlinear time-history analysis for seismic design and assessment of structures. The many available software tools should therefore be evaluated and well understood, in order to be easily and soundly employed by the practitioners. The study presented herein intends to contribute to this need by providing further insight with respect to the use of commonly employed structural analysis software tools in nonlinear analysis of bridge structures. A comparison between different nonlinear modeling assumptions is presented, together with the comparison with real experimental results. Furthermore, alternative adaptive pushover procedures are proposed and applied to a case study bridge, based on a generic plastic hinge model. The adopted structural analysis program proved to be accurate, yielding reliable estimates, both in terms of local plastic hinge behavior and global structural behavior.     

Fatigue crack in large-scale tubular joints for offshore structures

Tubular members have been used for constructing offshore structures. Large-scale fatigue tests of welded tubular K-joints under the balanced in-plane bending brace were carried out to investigate the fatigue behavior of API 2W Gr.50 steel produced by POSCO. The experimental results were verified by numerical approaches and compared with the IIW, DnV RP-C203 and API RP 2A-WSD design curves. The test results based on the hot spot stress were in agreement with the design curves. The SCF factor for tubular K-jo...     

Changes in blood flow velocity and diameter of the middle cerebral artery during hyperventilation: assessment with MR and transcranial Doppler sonography

PURPOSE: To compare blood flow velocity changes within the middle cerebral artery (MCA) during hyperventilation, as measured with by both transcranial Doppler sonography and MR imaging, with the diameter of the MCA as measured with MR imaging alone. METHODS: The studies were performed in six healthy volunteers ranging in age from 22 to 31 years (mean, 27 years). Transcranial Doppler sonography was carried out with a range-gated 2-MHz transducer. MR examinations were done on a 1.5-T imaging unit. MR angiography was performed using the time-of-flight technique. MR flow measurements were carried out by using the phase-mapping technique with an ECG-triggered phase-contrast sequence. RESULTS: During hyperventilation, the mean blood flow velocity of the proximal MCA declined by 49.6% +/- 5.7 (mean +/- standard deviation) as measured with Doppler sonography, and by 47% +/- 4.6 as measured with MR flow calculation. The diameter of the MCA (3.4 +/- 0.3 mm) remained unchanged on MR imaging studies (3.3 +/- 0.3 mm). CONCLUSION: We found a good correlation between relative flow velocity changes measured by transcranial Doppler sonography and MR techniques. MR imaging revealed no significant changes in the diameter of the proximal MCA during normal versus hyperventilation. Relative changes in flow velocity in the MCA would thereby reflect relative changes in cerebral blood flow, at least during hyperventilation.     

Effect of adenosine analogues on the expression of matrix metalloproteinases and their inhibitors from human dermal fibroblasts

The effect of the cytostatic and antiviral adenosine analogues 3-deazaadenosine (c3Ado) and 3-deaza-(+/-)-aristeromycin (c3Ari) on human skin fibroblasts was studied. Variables examined were cell morphology, viability, DNA fragmentation, expression of matrix metalloproteinases (MMPs) and matrix metalloproteinase inhibitors (TIMPs). None of these variables were changed when cells were exposed to c3Ari concentrations ranging from 10(-5) to 10(-3) M or 10(-5) M c3Ado. However, large changes in cell morphology, viability and expression of MMPs and MMP inhibitors occurred when fibroblasts were treated with 10(-4) or 10(-3) M c3Ado. Cells rounded up, shrank in volume, some detached and viability was lost without any detectable fragmentation of DNA. These changes in morphology and viability were associated with a differentiated expression of MMPs and MMP inhibitors. A large increase in collagenase activity occurred, and depending on the concentration of the adenosine analogue and the length of treatment, this change in activity could be shown to be due to one or a combination of the following factors: an increased synthesis of the collagenase protein, a decreased production of TIMP-1 or an increased activity of the collagenase superactivator, stromelysin. In contrast to this, treatment with c3Ado resulted in a decreased gelatinase activity, which in part could be attributed to an increased production of an inhibitor that seemed to affect gelatinase but not collagenase. The cellular changes induced by c3Ado seemed to reflect some of the alteration in the metabolic machinery that appears during a drug-induced or programmed/controlled death of a dermal cell. The different effects exerted by these two adenosine analogues on dermal fibroblasts can at least in part explain why c3Ado have previously been shown to be more toxic than c3Ari in animal models.     

Maternal immunization to Gov system alloantigens on human platelets

BACKGROUND: Immunization to platelet alloantigens can occur during pregnancy or after the transfusion of blood components. Platelet alloantibodies can cause neonatal alloimmune thrombocytopenia and posttransfusion purpura. Transfusion-induced alloimmunization to a novel platelet alloantigen system, Gov, expressed on the 175-kDa glycosyl phosphatidylinositol-anchored platelet glycoprotein, CD109, was previously described. This report describes three unrelated patients who were alloimmunized to Gov(a) or Gov(b) during pregnancy. STUDY DESIGN AND METHODS: Platelets were typed by using radioimmunoprecipitation for HPA-1a, -3a, -5a, -5b, Gov(a), and Gov(b) and by polymerase chain reaction-restriction fragment length polymorphism for HPA-1a, -1b, -3a, and -3b. Maternal sera were screened for platelet antibodies by using radioimmunoprecipitation and the antigen capture assay. RESULTS: Patients 1 and 2 were investigated after the diagnosis of neonatal alloimmune thrombocytopenia in their children, and alloantibodies specific for Gov(b) and Gov(a), respectively, were detected in maternal serum. Serum from patient 3, who had mild idiopathic thrombocytopenia purpura with no detectable autoantibody, was found to contain alloantibodies to Gov(b) and to HPA-5b, presumably as a result of immunization during pregnancy. Platelet typings confirmed that the patients were at risk for alloimmunization to the respective antigen. CONCLUSION: This report of three cases of maternal alloimmunization to antigens in the Gov system indicates that immunization can occur via placental transfer of antigen and that Gov system alloantibodies may be associated with neonatal alloimmune thrombocytopenia.     

Localization of Xenopus Vg1 mRNA by Vera protein and the endoplasmic reticulum

In many organisms, pattern formation in the embryo develops from the polarized distributions of messenger RNAs (mRNAs) in the egg. In Xenopus, the mRNA encoding Vg1, a growth factor involved in mesoderm induction, is localized to the vegetal cortex of oocytes. A protein named Vera was shown to be involved in Vg1 mRNA localization. Vera cofractionates with endoplasmic reticulum (ER) membranes, and endogenous Vg1 mRNA is associated with a subcompartment of the ER. Vera may promote mRNA localization in Xenopus oocytes by mediating an interaction between the Vg1 3' untranslated region and the ER subcompartment.     

Altered receptive fields and sensory modalities of rat VPL thalamic neurons during spinal strychnine-induced allodynia

Altered receptive fields and sensory modalities of rat VPL thalamic neurons during spinal strychnine-induced allodynia. J. Neurophysiol. 78: 2296-2308, 1997. Allodynia is an unpleasant sequela of neural injury or neuropathy that is characterized by the inappropriate perception of light tactile stimuli as pain. This condition may be modeled experimentally in animals by the intrathecal (i.t.) administration of strychnine, a glycine receptor antagonist. Thus after i.t. strychnine, otherwise innocuous tactile stimuli evoke behavioral and autonomic responses that normally are elicited only by noxious stimuli. The current study was undertaken to determine how i.t. strychnine alters the spinal processing of somatosensory input by examining the responses of neurons in the ventroposterolateral thalamic nucleus. Extracellular, single-unit recordings were conducted in the lateral thalamus of 19 urethan-anaesthetized, male, Wistar rats (342 +/- 44 g; mean +/- SD). Receptive fields and responses to noxious and innocuous cutaneous stimuli were determined for 19 units (1 per animal) before and immediately after i.t. strychnine (40 microgram). Eighteen of the animals developed allodynia as evidenced by the ability of otherwise innocuous brush or air jet stimuli to evoke cardiovascular and/or motor reflexes. All (3) of the nociceptive-specific units became responsive to brush stimulation after i.t. strychnine, and one became sensitive to brushing over an expanded receptive field. Expansion of the receptive field, as determined by brush stimulation, also was exhibited by all of the low-threshold mechanoreceptive units (14) and wide dynamic range units (2) after i.t. strychnine. The use of air jet stimuli at fixed cutaneous sites also provided evidence of receptive field expansion, because significant unit responses to air jet developed at 13 cutaneous sites (on 7 animals) where an identical stimulus was ineffective in evoking a unit response before i.t. strychnine. However, the magnitude of the unit response to cutaneous air jet stimulation was not changed at sites that already had been sensitive to this stimulus before i.t. strychnine. The onset of allodynia corresponded with the onset of the altered unit responses (i.e., lowered threshold/receptive field expansion) for the majority of animals (9), but the altered unit response either terminated concurrently with symptoms of allodynia (6) or, more frequently, outlasted the symptoms of allodynia (10) as the effects of strychnine declined. The present results demonstrate that the direct, receptor-mediated actions of strychnine on the spinal processing of sensory information are reflected by changes in the receptive fields and response properties of nociceptive and nonnociceptive thalamic neurons. These changes are consistent with the involvement of thalamocortical mechanisms in the expression of strychnine-induced allodynia and, moreover, suggest that i.t. strychnine also produces changes in innocuous tactile sensation.