High-dose cytarabine and daunorubicin as consolidation therapy for acute myeloid leukemia in first remission: long-term follow-up and results

In an effort to increase the proportion of patients with acute myeloid leukemia (AML) remaining in continued complete remission (CCR), we administered intensive postremission consolidation therapy with high-dose cytarabine (Ara-C) and daunorubicin. Eighty-seven patients, with a median age of 38 years (range, 7 to 71), received consolidation therapy after first complete remission was obtained with standard induction chemotherapy that included conventional doses of Ara-C. Consolidation therapy consisted of from one to three cycles of high-dose Ara-C (3 g/m2 intravenously [IV] over 1 hour every 12 hours for 12 doses) followed by daunorubicin (30 mg/m2/d IV bolus for 3 days). After completion of the high-dose Ara-C and daunorubicin, no further therapy was administered. Myelosuppression encountered with consolidation resulted in a median duration of neutropenia and thrombocytopenia of 3 weeks. Four patients (5%) died during consolidation due to infection and/or hemorrhage; 59% of patients experienced severe but nonfatal infectious or extramedullary organ toxicity. With a median follow-up of more than 3.5 years from diagnosis, the proportion of patients, by Kaplan-Meier product-limit estimate, remaining in CCR is 49% (95% confidence limits, 37% to 61%). In a Cox multivariate analysis, only age significantly (P less than .001) influenced the probability of remaining in CCR. The probability of remaining in CCR was 83%, 50%, and 23% for age groups of 25 or less, 26 to 45, and more than 45 years, respectively. These survival curves all have stable long-term plateaus, suggesting cure. In this study, the administration of brief, intensive nonmarrow ablative chemotherapy resulted in a large proportion of patients with AML remaining in CCR, results similar to those reported with allogeneic bone marrow transplantation. Relapse of acute leukemia was still the major reason for therapy failure, suggesting that more effective or additional postremission therapy will be required to further improve the likelihood of cure especially for older patients.     

Identification of a binding site on human FGF-2 for fibrinogen

Endothelial cell adhesive interactions are mediated by both fibrinogen and fibrin, and growth is stimulated by fibroblast growth factor 2 (FGF-2). We have shown previously that FGF-2 binds specifically and with high affinity to fibrinogen and fibrin and that fibrinogen potentiates the proliferative capacity of FGF-2 and also protects it from proteolytic degradation. To further characterize this interaction we have performed FGF-2 mutagenesis to identify the interactive site. Because FGF-1 has a similar structure to FGF-2 but does not bind to fibrinogen, we used a strategy of cassette and site-directed mutagenesis, exchanging residues from FGF-1 and FGF-2 and correlating structural changes with fibrinogen binding. Two cassette interchange mutants, 2212 and 2211, contained either the third cassette or both the third and fourth cassettes from FGF-1, and neither exhibited any affinity for fibrinogen. Exchange of 5 residues (Phe95, Ser100, Asn102, Arg107, and Arg109) from FGF-2 into the corresponding sites in the third cassette of FGF-1 imparted high-affinity binding with apparent dissociation constants (Kd) of 5.3 nM and 8.6 nM, respectively, compared with 1.3 nM for wild-type FGF-2. We conclude that these 5 residues define a high-affinity binding site in FGF-2 for fibrinogen.     

Long-term results of renal transplantation using kidneys harvested from non-heartbeating donors: a 15-year experience

PURPOSE: To expand the pool of suitable organ donors we developed an organ procurement program of non-heartbeating donors during the last 15 years. We compare graft survival in patients receiving renal transplants procured from non-heartbeating with recipients of kidneys from heartbeating donors. MATERIALS AND METHODS: From 1986 to 1999, 60 renal transplantations were performed with kidneys harvested from non-heartbeating donors (Mastrich category IV). Kidneys were procured using a double balloon triple lumen catheter inserted into the femoral artery. The 60 kidneys were selected from 70 non-heartbeating donors based on age younger than 50 years, warm ischemia less than 30 minutes, creatinine less than 200 micromol./l., and no hypertension or major histological lesions. Long-term results of graft survival and complications were compared with a series of 1,065 renal transplantations performed during the same period with kidneys procured from heartbeating donors. RESULTS: Mean age of the recipients was statistically different as non-heartbeating donors were older. However, the 10-year graft survival rates were similar in both groups (50% versus 53%). Incidence of ureteral stenosis and fistula, arterial stenosis and thrombosis was not statistically different in both groups. On the other hand, delay graft function was more frequent in non-heartbeating donors (60% versus 40%, p = 0.01). CONCLUSIONS: Despite a high rate of acute tubular necrosis, kidneys harvested from non-heartbeating donors had the same graft survival rates as those procured from heartbeating donors. Surgical complications were not different. Transplantation of selected kidneys procured from non-heartbeating donors should be promoted as a response to organ shortage.     

Head and body center of gravity control strategies: adaptations following vestibular rehabilitation

OBJECTIVE: We present for the first time evidence that vestibulopathy impairs coordination of the head with the body center of gravity (CG) during free speed gait over ground. Vestibulopathic individuals demonstrate uncoordinated movement and gait due, at least in part, to impaired head stability and visual fixation. Vestibular rehabilitation increases speed and stability during gait and stair climbing, although the underlying mechanisms are poorly understood. MATERIAL AND METHODS: To determine whether these locomotor improvements are due to reorganized coordination of the head with whole body CG, three-dimensional kinematics were obtained from 10 vestibulopathic individuals before and after vestibular rehabilitation and from 10 matched healthy control subjects during unconstrained, paced and in-place gait. Head control patterns were characterized using both qualitative pattern analysis and quantification of coherence between head and body CG displacements. RESULTS: Patterns of head-CG coordination differ between normal and vestibulopathic individuals in all three directions of head rotation--pitch, roll and yaw--before rehabilitation. Following vestibular rehabilitation, subjects with vestibulopathy demonstrate more normal patterns in pitch and improvements toward normal in roll and yaw. CONCLUSION: These data strongly suggest that compensatory mechanisms, obtained during vestibular rehabilitation, mediate head-CG coordination.     

Immunological study in sickle cell disease patients: importance of the complement system

Ten Tunisian patients, with homozygote sickle cell disease and asplenia were studied to investigate and to determine possible immunological function defects. Obtained results directed us to an abnormality of the alternate complement pathway activation which is expressed by a decreased hémolytic activity, while the classic pathway is normal. Quantification of C3, C4, C5, C6, C7 and factor B by immunochemical assay were normal, whereas factor B functional activity was depressed to a mean level of about half of normal in eight patients, IgG was increased in one subject and IgA in two others. Numeration of Band T cells revealed slight decrease in proportion of CD3 and CD4 at one patient associated with an increase in B cells, but normal or increased absolute numbers of all cells population.     

Perception of two-tone complexes by the goldfish (Carassius auratus)

Previous experiments on the sense of hearing in goldfish have used a stimulus generalization paradigm to investigate the perceptual dimensions evoked by spectrally and temporally complex sounds. The present experiments investigated the effects on perception of the frequency separation between two tones. In the first set of experiments, six groups of goldfish were classically conditioned to a single tone and then tested for generalization to two-tone complexes having one frequency component equal to the conditioning tone, and the other differing by 2–256 Hz. Generalization declined with increasing frequency differences up to about 32 Hz, and then increased for wider frequency separations. These functions indicate that a restricted range of beat rates produces a perceptual quality that is quite unlike that of a single tone. The generalization function of frequency separation resembles the inverse of the ‘fluctuation strength' and ‘roughness' functions for human listeners. The second experiment investigated the effects of spectral location on the perception of a 32 Hz beat rate. Goldfish were conditioned to a two-tone complex (500 and 532 Hz) and then tested for generalization to single tones at various frequencies between 200 and 1200 Hz, and to two-tone complexes having a 32 Hz beat rate but with the lower tone component at various frequencies. For single-tone stimuli, generalization was relatively weak but showed a peak at 500 Hz. For the two-tone stimuli, generalization was more robust, but showed a similarly shaped gradient centered on 500 Hz. Thus, goldfish behaved as if they had acquired information about both temporal modulation and the frequency location of the tone components. These perceptual behaviors appear to be shared with humans and other vertebrates.     

Permutation tests for joinpoint regression with applications to cancer rates

The identification of changes in the recent trend is an important issue in the analysis of cancer mortality and incidence data. We apply a joinpoint regression model to describe such continuous changes and use the grid-search method to fit the regression function with unknown joinpoints assuming constant variance and uncorrelated errors. We find the number of significant joinpoints by performing several permutation tests, each of which has a correct significance level asymptotically. Each p-value is found using Monte Carlo methods, and the overall asymptotic significance level is maintained through a Bonferroni correction. These tests are extended to the situation with non-constant variance to handle rates with Poisson variation and possibly autocorrelated errors. The performance of these tests are studied via simulations and the tests are applied to U.S. prostate cancer incidence and mortality rates.