Costs after hip fracture in independently living patients: a randomised comparison of three rehabilitation modalities.

OBJECTIVE: To evaluate costs and cost-effectiveness of physical and geriatric rehabilitation after hip fracture. DESIGN: Prospective randomised study (mean age 78 years, 105 male, 433 female) in different rehabilitation settings: physically oriented (187 patients), geriatrically oriented (171 patients), and healthcare centre hospital (control, 180 patients). MAIN MEASURES: At 12 months post-fracture, we collected data regarding days in rehabilitation, post-rehabilitation hospital treatment, other healthcare service use, number of re-operations, taxi use by patient or relative, and help from relatives. RESULTS: Control rehabilitation (4945,2€) was significantly less expensive than physical (6609.0€, p=0.002) and geriatric rehabilitation (7034.7€ p<0.001). Total institutional care costs (primary treatment, rehabilitation, and post-rehabilitation hospital care) were lower for control (13,438.4€) than geriatric rehabilitation (17,201.7€, p<0.001), but did not differ between control and physical rehabilitation (15659.1€, p=0.055) or between physical and geriatric rehabilitation ( p=0.252). Costs of help from relatives (estimated as 30%, 50% and 100% of a home aid's salary) with physical rehabilitation were lower than control ( p=0.016) but higher than geriatric rehabilitation ( p=0.041). Total hip fracture treatment costs were lower with physical (36,356€, 51,018€) than control rehabilitation (38,018€, 57,031€) at 50% and 100% of salary ( p=0.032, p=0.014, respectively). At one year post-fracture, 15D-score was significantly higher in physical rehabilitation group (0.697) than geriatric rehabilitation group (0.586, p=0.008) and control group (0.594, p=0.009). CONCLUSIONS: Considering total costs one year after hip fracture the treatment including physical rehabilitation is significantly more cost-effective than routine treatment. This effect could not be seen between routine treatment and treatment including geriatric rehabilitation.

Economic evaluation of exercise-based cardiac rehabilitation in patients with a recent acute coronary syndrome.

Health care decision-making requires evidence of the cost-effectiveness of medical therapies. We evaluated the cost-effectiveness of exercise-based cardiac rehabilitation (ECR) implemented according to guidelines. All the patients (n = 204) had experienced a recent acute coronary syndrome and were randomized to a 1-year ECR (n = 109) or usual care (UC) group (n = 95). The patients' health-related quality of life was followed using the 15D instrument and health care costs were collected from electronic health registries. The cost-effectiveness of ECR was estimated based on intervention and health care costs and quality-adjusted life years (QALYs) gained. The total average cost per patient was lower in ECR than in UC. The incremental cost was divided by the baseline-adjusted incremental QALYs (0.045), yielding an incremental cost-effectiveness ratio of -€24511/QALYs. A combined endpoint of mortality, recurrent coronary event, or hospitalization for a heart failure occurred for five patients in ECR and 16 patients in UC (HR 3.9, 95% CI 1.4-10.6, P = 0.004, relative risk reduction 73%, number needed to treat eight). ECR is a dominant treatment option and decreases the occurrence of adverse cardiac events. These results are useful for decision-making when planning optimal utilization of resources in Finnish health care.

Proteome changes in tomato lines transformed with phytoene synthase-1 in the sense and antisense orientations.

The commercial cultivation of genetically engineered (GE) crops in Europe has met with considerable consumer resistance, which has led to vigorous safety assessments including the measurement of substantial equivalence between the GE and parent lines. This necessitates the identification and quantification of significant changes to the metabolome and proteome in the GE crop. In this study, the quantitative proteomic analysis of tomato fruit from lines that have been transformed with the carotenogenic gene phytoene synthase-1 (Psy-1), in the sense and antisense orientations, in comparison with a non-transformed, parental line is described. Multidimensional protein identification technology (MudPIT), with tandem mass spectrometry, has been used to identify proteins, while quantification has been carried out with isobaric tags for relative and absolute quantification (iTRAQ). Fruit from the GE plants showed significant alterations to their proteomes compared with the parental line, especially those from the Psy-1 sense transformants. These results demonstrate that MudPIT and iTRAQ are suitable techniques for the verification of substantial equivalence of the proteome in GE crops.

Bayesian adaptive Markov chain Monte Carlo estimation of genetic parameters.

Accurate and fast estimation of genetic parameters that underlie quantitative traits using mixed linear models with additive and dominance effects is of great importance in both natural and breeding populations. Here, we propose a new fast adaptive Markov chain Monte Carlo (MCMC) sampling algorithm for the estimation of genetic parameters in the linear mixed model with several random effects. In the learning phase of our algorithm, we use the hybrid Gibbs sampler to learn the covariance structure of the variance components. In the second phase of the algorithm, we use this covariance structure to formulate an effective proposal distribution for a Metropolis-Hastings algorithm, which uses a likelihood function in which the random effects have been integrated out. Compared with the hybrid Gibbs sampler, the new algorithm had better mixing properties and was approximately twice as fast to run. Our new algorithm was able to detect different modes in the posterior distribution. In addition, the posterior mode estimates from the adaptive MCMC method were close to the REML (residual maximum likelihood) estimates. Moreover, our exponential prior for inverse variance components was vague and enabled the estimated mode of the posterior variance to be practically zero, which was in agreement with the support from the likelihood (in the case of no dominance). The method performance is illustrated using simulated data sets with replicates and field data in barley.

Blood stream infections during chemotherapy-induced neutropenia in adult patients with acute myeloid leukemia: treatment cycle matters.

The purpose of this study was to assess the frequency of blood stream infections (BSIs) during neutropenia in different cycles of intensive chemotherapy treatment in acute myeloid leukemia (AML). The register data of 327 consecutive patients aged 16-66 years having de novo AML between September 1992 and December 2001 were prospectively gathered in five Finnish tertiary care leukemia centers. The patients had not received fluoroquinolone prophylaxis. Reported BSI rates were compared during neutropenia in four chemotherapy treatment cycles (C). There were 956 treatment episodes, with 456 (47.7%) positive blood cultures. BSI was monomicrobial in 327 episodes (71.7%) and polymicrobial in 129 (28.3%). The overall incidence rate (per 1,000 hospital days) for BSI was 13.2, varying from 6.8 in CI after idarubicin, conventional-dose cytarabine, and thioguanine to 15.6 in CII, 15.8 in CIII, and 17.6 in CIV. The distribution of monomicrobial gram-positive BSIs was as follows: CI, 71.7%; CII, 62.8%; CIII, 53.3%; CIV, 36.6%; and CI-IV together, 43.2%. The most common finding in the four different cycles was coagulase-negative staphylococci (38.3 to 30.6%). Viridans group streptococci were most commonly observed (in 20.4% of positive blood cultures) during CII after high-dose cytarabine and idarubicin treatments. The distribution of monomicrobial gram-negative BSIs was as follows: CI, 21.7%; CII, 36.3%; CIII, 45.7%; CIV, 46.9%; and CI-IV together, 37.9%. A great variation of incidence and types of microorganisms between AML chemotherapy cycles was found. It would be more reasonable to analyze chemotherapy cycle-based BSI results rather than the overall results.

Idarubicin inhibits the growth of bacteria and yeasts in an automated blood culture system.

The effect of anti-neoplastic agents on the growth of microorganisms was studied in vitro using aerobic BacT/Alert standard and FAN bottles as the culture media. A 50% longer incubation period to detect microbial growth compared to the control group was interpreted as growth inhibition. Idarubicin inhibited the growth of all of the five gram-positive cocci, one of five gram-negative rods and one of three yeast strains studied in the standard bottles but not in the FAN bottles. Candida glabrata was the most sensitive strain. Its growth was inhibited in the presence of idarubicin at a concentration of 1 micromol/l.

Blood stem cell mobilization and collection in patients with chronic lymphocytic leukaemia: a nationwide analysis.

Some reports suggest that blood stem cell mobilization is difficult in a proportion of patients with CLL. We evaluated this issue in a large cohort of CLL patients. One hundred and twenty-eight patients with CLL underwent blood stem cell mobilization during 1995-2005 in Finland. Ninety-five percent of the patients had received fludarabine. The most common mobilization regimen was intermediate-dose CY plus G-CSF (90 patients, 70%). At least 2 x 10(6)/kg CD34+ cells were collected after the first mobilization attempt in 83 patients (65%), whereas 45 patients (35%) failed to reach this collection target. No differences were observed between these patient groups with regard to age, time from the diagnosis to mobilization, number of previous treatment lines, number of fludarabine courses, time from the last fludarabine-containing chemotherapy to mobilization, disease status or degree of marrow infiltration. Patients who failed collection had platelets <100 x 10(9)/l more commonly at the time of mobilization (30 vs 4%, P<0.001). A significant proportion of patients with CLL were difficult to mobilize. Adequate marrow function including platelet counts >100 x 10(9)/l seem to be important factors in terms of successful blood stem cell collection.

Late non-relapse mortality among adult autologous stem cell transplant recipients: a nation-wide analysis of 1,482 patients transplanted in 1990-2003.

Data on the incidence and causes of late (>100 d) non-relapse mortality (NRM) in autologous stem cell transplant (ASCT) recipients is limited. We have analysed NRM in a cohort of 1,482 adult patients who received ASCT in 1990-2003 in six Finnish transplant centres. The most common diagnoses included non-Hodgkin's lymphoma (NHL) (n = 542), multiple myeloma (MM) (n = 528), breast cancer (n = 132); Hodgkin's lymphoma (HL) (n = 86) and chronic lymphocytic leukaemia (CLL) (n = 63). Until September 2005, 646 patients (44%) have died. Late NRM was observed in 68 patients (4.6% of ASCT recipients; 11% of all deaths). There were 38 males and 30 females with a median age of 58 yr (20-69) at the time of ASCT. The median time to NRM was 27 months from ASCT (3-112). The risk of NRM was highest in patients with CLL (9.5%) and those with HL (8.1%) followed by MM and NHL (4.9% and 4.8%, respectively). The risk of late NRM was comparable in patients who received total body irradiation (TBI) and those who received chemotherapy-only regimens (6.7% vs. 4.3%). Another malignancy was the most common cause of late NRM (24 patients, 35% of late NRM). Twelve patients (0.8% of ASCT recipients) have died due to secondary haematological malignancy. Altogether 22 patients (32% of late NRM) died from infectious causes. Malignancies and late infections are important causes of NRM after ASCT. These facts point out the importance of prolonged follow-up in ASCT recipients.

Autologous stem cell transplantation in patients with chronic lymphocytic leukaemia: the Finnish experience.

Although autologous stem cell transplantation (ASCT) has gained some popularity as a treatment option in patients with chronic lymphocytic leukaemia (CLL), limited multicentre data are available on the feasibility and efficacy of this approach. Between January 1995 and June 2005, 72 patients with CLL received ASCT in five Finnish centres. There were 45 men and 27 women with a median age of 57 years (38-69). The median time from diagnosis to ASCT was 32 months (6-181) and the median number of prior regimens 1 (1-4). All patients received blood stem cell grafts and CD34+ selection had been performed in 44 patients (61%). The most common high-dose regimen was a total body irradiation plus cyclophosphamide (38 patients, 53%). No early treatment-related deaths were observed. With a median follow-up of 28 months from ASCT, a relapse or progression has been observed in 27 patients (37%). The projected progression-free survival is 48 months (confidence interval (CI) 30-66). The projected median overall survival is 95 months (CI 74-101) from ASCT and is not influenced by graft selection or conditioning regimen used. Autologous stem cell transplantation is a feasible treatment option for CLL. Randomized trials against alternative treatments are needed to assess the impact of ASCT on the clinical course of CLL.

Early treatment-related mortality in adult autologous stem cell transplant recipients: a nation-wide survey of 1482 transplanted patients.

OBJECTIVES: To evaluate early (<100 d) treatment-related mortality (TRM) in autologous stem cell transplant (ASCT) recipients. PATIENTS: Altogether 1482 adult patients received ASCT in six Finnish centres 1990-2003. The most common diagnoses were non-Hodgkin's lymphoma (NHL) (n = 542), multiple myeloma (MM) (n = 528), breast cancer (BC) (n = 132), Hodgkin's lymphoma (n = 86) and chronic lymphocytic leukaemia (CLL) (n = 63). RESULTS: Forty-two patients (2.8%) died from treatment-related reasons <100 d from ASCT. The median time to death was 38 d from ASCT (0-99). The risk of TRM varied according to the diagnoses. The highest risk was observed in patients with AL amyloidosis (24%) followed by NHL (4.4%) and MM (1.9%). No early TRM was observed in patients transplanted for BC or CLL. Infections were the cause of death in 16 patients (fungal 7, bacterial 6, viral 3). Organ toxicity was responsible for early death in 26 patients (heart 9, lungs 7, other 10). CONCLUSIONS: This nation-wide survey indicated a low early TRM in ASCT recipients in general, but higher risks in patients with AL amyloidosis or NHL. In addition to patient selection, also optimization of transplant procedure may be needed in these patient groups to reduce early TRM.

Activation and relocalization of caspase 3 during the apoptotic cascade of human mesothelioma cells.

Apoptosis plays an important role in cancer biology. We investigated the expression of caspases 3 and 8 in malignant mesothelioma and malignant mesothelioma cell lines and putative changes in their ultrastructural expression prior and after exposure to epirubicin. Further studies were conducted to compare these changes to the localization and expression of the bcl-2 group of proteins bcl-X, bax and mcl-1, and Fas-Fas ligand in the same cells. In the histological samples, caspase 3 and 8 immunoreactivity was seen in 27/37 (73%) and 16/37 (43%) of the mesotheliomas. The immunostaining was cytoplasmic diffuse, granular, and occasionally nuclear. All six mesothelioma cell lines expressed caspases 3 and 8 by immunoblotting. After exposure to epirubicin the extent of apoptosis was increased in all cell lines investigated, being weakest in the most resistant M38K cell line. Immunoelectron microscopy revealed immunogold labeling for caspases 3 and 8 in the mitochondria with the accumulation of caspase 3 in the apoptotic bodies, while the mitochondrial localization of the bcl-2 proteins appeared to be very stable. Fas receptor could be detected by flow cytometry, whereas the most resistant cell line (M38K) lacked Fas ligand when assessed by RT-PCR. These results suggest the importance of caspase 3 during the apoptotic process of mesothelioma cells and indicate that epirubicin-induced apoptosis is independent of the mitochondrial pathway.

Stability of Thought Disorder Index among high-risk and low-risk adoptees in the Finnish adoptive family study of schizophrenia.

The aim of the study was to evaluate whether thought disorders are stable, trait-like features specific to subjects who have a genetic liability to schizophrenia or a psychiatric disorder. The thought disorders of adoptees genetically at high risk (HR) or low risk (LR) for schizophrenia from the Finnish adoptive family study of schizophrenia were evaluated twice at a mean interval of 11 years, using the sum of the Thought Disorder Index (TDI) scores on the Rorschach (TD(R)). At the initial assessment, the mean TD(R) scores of women were significantly higher than those of men, while no association between genetic risk and psychiatric status or their interactions with the TD(R) scores at baseline were found. The main finding was that the initial TD(R) scores statistically significantly predicted the TD(R) scores at follow-up, thus indicating the stability of thought disorder over time. However, neither genetic or psychiatric status nor gender or any interaction between these variables associated with TD(R) at follow-up.

Autologous stem cell transplantation in patients with primary amyloidosis: a nation-wide survey.

Due to poor prognosis with conventional therapy, high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is considered for treatment in patients with primary amyloidosis (AL). Only single centre series are available on the feasibility and efficacy of this approach. Altogether 20 AL patients (11 males, 9 females, median age 54 years) were included in HDT protocols in 5 Finnish transplant centres between 1997 and 2003. Twelve patients were mobilized with granulocyte colony-stimulating factor (G-CSF) alone and 8 patients with a combination of cyclophosphamide and G-CSF. Sixteen patients (80%) went on to high-dose melphalan. Early transplant-related mortality was 25%. Nine out of 11 evaluable patients showed improvement or stabilization of AL. The overall survival of the transplanted patients is 69% (median follow-up 13 months). After a median follow-up of 26 months for the living patients, only 2 patients (18%) have shown progression of AL. This retrospective nation-wide analysis shows that HDT with ASCT leads to improvement or stabilization of AL in the majority of the patients who survive the immediate posttransplant period. A randomized multicentre trial is needed to show whether ASCT is superior to conventional therapy in patients with AL.

Two functional variants of the superoxide dismutase genes in Finnish families with asthma.

BACKGROUND: Functional polymorphisms in the genes encoding superoxide dismutases (SOD)-that is, superoxide scavenging antioxidant enzymes-may play an important role in the development of inflammatory airway diseases such as asthma. METHODS: The allele frequencies of two missense polymorphisms of SOD genes (Ala16Val in MnSOD (SOD2) and Arg213Gly in ECSOD (SOD3)) were investigated in Finnish patients with asthma and compared with family based controls. Both variants have been shown to be functionally interesting in the lung. The polymorphism at the exon-intron 3 boundary of a third SOD, CuZnSOD (SOD1), was also included in the analysis. RESULTS: None of the SOD genetic variants studied appeared to be major genetic regulators in the development of asthma. We could exclude all models of inheritance that increased the risk of asthma more than 1.2 fold for MnSOD*Val (frequency of allele 0.74 in the population) and more than 6.6 fold for ECSOD*Gly213 (frequency of allele 0.03 in the population) compared with non-carriers. For the intronic polymorphism in CuZnSOD, a relative risk of more than 3.3 (frequency of allele 0.10 in the population) could be excluded. CONCLUSIONS: It is highly unlikely that the functionally important genetic variants Ala16Val and Arg213Gly of SODs play a major role in the genetic susceptibility of asthma.

Oral treatment of acute myeloid leukaemia with etoposide, thioguanine, and idarubicin (ETI) in elderly patients: a prospective randomised comparison with intravenous cytarabine, idarubicin, and thioguanine in the second and third treatment cycle.

A randomised multicentre study was conducted among patients over 65 yr of age with newly diagnosed acute myeloid leukaemia (AML) to compare oral treatment with etoposide 80 mg/m(2) and thioguanine 100 mg/m(2) twice daily on 5 d and idarubicin 15 mg/m(2) on 3 d (ETI) to a mainly i.v. combination of cytarabine 100 mg/m(2) twice daily on 5 d, idarubicin 12 mg/m(2) x 1, and thioguanine (TAI). Ninety-two patients were enrolled. Their median age was 72 yr, range 65-84 yr. Sixty-five patients had de novo AML, 21 AML subsequent to myelodysplastic syndrome, and six treatment-related AML. They received at first a 6-d i.v. treatment with cytarabine and idarubicin. After the first treatment, 68 patients were randomised to receive two cycles of ETI (n = 36) or TAI (n = 32) and thereafter maintenance with mercaptopurine and methotrexate. Of the 92 patients, 52 (57%) achieved remission at some stage. The median survival was 10 months. There were no significant differences between the patients randomised to ETI or TAI in the remission rate (67% vs. 72%), survival (12 months from randomisation in both arms), event-free survival or relapse rate. The patients randomised to receive ETI spent significantly fewer days at hospital during the two randomised cycles (20 vs. 41 d, P = 0.010), and they had fewer days with infusions, shorter neutropenias and thrombocytopenias and fewer and less severe infections. In conclusion, treatment with oral ETI resulted in a similar antileukaemic effect as obtained with mainly i.v. TAI, with less toxicity and reduced need for hospitalisation.

Statistical inversion for medical x-ray tomography with few radiographs: I. General theory.

In x-ray tomography, the structure of a three-dimensional body is reconstructed from a collection of projection images of the body. Medical CT imaging does this using an extensive set of projections from all around the body. However, in many practical imaging situations only a small number of truncated projections are available from a limited angle of view. Three-dimensional imaging using such data is complicated for two reasons: (i) typically, sparse projection data do not contain sufficient information to completely describe the 3D body, and (ii) traditional CT reconstruction algorithms, such as filtered backprojection, do not work well when applied to few irregularly spaced projections. Concerning (i), existing results about the information content of sparse projection data are reviewed and discussed. Concerning (ii), it is shown how Bayesian inversion methods can be used to incorporate a priori information into the reconstruction method, leading to improved image quality over traditional methods. Based on the discussion, a low-dose three-dimensional x-ray imaging modality is described.

Statistical inversion for medical x-ray tomography with few radiographs: II. Application to dental radiology.

Diagnostic and operational tasks in dental radiology often require three-dimensional information that is difficult or impossible to see in a projection image. A CT-scan provides the dentist with comprehensive three-dimensional data. However, often CT-scan is impractical and, instead, only a few projection radiographs with sparsely distributed projection directions are available. Statistical (Bayesian) inversion is well-suited approach for reconstruction from such incomplete data. In statistical inversion, a priori information is used to compensate for the incomplete information of the data. The inverse problem is recast in the form of statistical inference from the posterior probability distribution that is based on statistical models of the projection data and the a priori information of the tissue. In this paper, a statistical model for three-dimensional imaging of dentomaxillofacial structures is proposed. Optimization and MCMC algorithms are implemented for the computation of posterior statistics. Results are given with in vitro projection data that were taken with a commercial intraoral x-ray sensor. Examples include limited-angle tomography and full-angle tomography with sparse projection data. Reconstructions with traditional tomographic reconstruction methods are given as reference for the assessment of the estimates that are based on the statistical model.

IL-1 RN 2/2 genotype and simultaneous carriage of genotypes IL-1 RN 2/2 and IL-1beta-511 T/T associated with oesophagitis in Helicobacter pylori-negative patients.

BACKGROUND: Interleukin-1 receptor antagonist genotype 2/2 is associated with a prolonged and enhanced inflammatory response. It is suspected of being a risk factor for atrophic gastritis and gastric cancer and for some autoimmune diseases. No specific genetic risk factors for oesophagitis have been identified so far and there are no reports of IL-1 polymorphism in relation to oesophageal disease. METHODS: We studied the IL-1RN, IL-1beta-511 and IL-1beta + 3953 polymorphisms in an unselected series of 142 adult patients scheduled for gastrointestinal endoscopy because of dyspepsia. The control group consisted of university staff and students (n = 179). Helicobacter pylori status was determined by antibody testing and bacterial detection. RESULTS: Endoscopic oesophagitis was noted in 40 patients. The IL-1RN 2/2 genotype was significantly more prevalent in the patients with H. pylori-negative oesophagitis than in the control subjects (27% versus 9%; OR 3.574, CI 1.23-10.35, P = 0.034) or in the dyspeptic patients (27% versus 7%; OR 5.089. CI 1.51-17.11, P = 0.009). IL-1beta-511 T/T genotype tended to be more frequent in the H. pylori-negative patients with oesophagitis than in the control subjects (P = 0.071). The strongest association was between the simultaneous carriage of genotypes IL-1RN 2/2 and IL-1beta -511 T/T and H. pylori-negative oesophagitis. where the combined genotype was more prevalent than in the control subjects (23% versus 6%; OR 4.492, CI 1.40-14.46, P = 0.012) or the dyspeptic patients without oesophagitis (23% versus 3%: OR 9.706. CI 2.12-44.42, P = 0.003). CONCLUSIONS: The results indicate that the IL-1RN 2/2 genotype and the carriage of combined genotypes IL-1RN 2/2 + IL-1beta-511 T/T are associated with H. pylori-negative oesophagitis. This is the first report on the association between IL-1 gene polymorphism and oesophagitis.

Effect of CD14 promoter polymorphism and H. pylori infection and its clinical outcomes on circulating CD14.

CD14 is a pattern recognition receptor on the membranes of monocytes and macrophages for several microbial products, of which lipopolysaccharide (LPS) is the best known. A shed form of CD14 is present in serum. As the CD14 gene promoter polymorphism -159C/T and some bacterial infections may affect the sCD14 levels, we compared the impact of both the CD14 promoter polymorphism and Helicobacter pylori infection on serum sCD14 levels in 201 dyspeptic patients (group 1) who had undergone gastroscopy, and 127 staff members (group 2) with no endoscopy. sCD14 was measured from the sera by a commercial enzyme immunoassay (EIA), and CD14 genotyping was carried out with PCR. Helicobacter pylori infection was detected by serology and/or culture or PCR. sCD14 levels were elevated in the subjects carrying the T allele (CT or TT genotype) in both groups when compared with subjects with the CC genotype. Overall, H. pylori-positive subjects tended to have higher sCD14 levels compared with H. pylori-negative subjects. In group 1 consisting of dyspeptic patients, those with gastric ulcer, gastric erosion or duodenal ulcer had significantly elevated levels of sCD14 compared with the patients with normal endoscopic findings or macroscopic gastritis. The recent use of NSAIDs was also associated with enhanced sCD14. Thus, we were able to show several factors, one genetic and the other environmental (H. pylori infection and mucosal lesion), to have an impact on sCD14.

p53 and redox state in etoposide-induced acute myeloblastic leukemia cell death.

We investigated whether p53, being a redox-sensitive protein, has a role in the responsiveness of AML cells to etoposide. Two subclones of the OCI/AML-2 cell line, the etoposide-sensitive (ES) and the etoposide-resistant (ER), were used as models. Sensitivity to etoposide was measured by trypan blue and annexin V assays. Etoposide-induced peroxide formation was associated with the induction of cell death. Evident expression of mutated p53 was observed in both subclones in basal growth conditions as analysed by Western blotting and flow cytometry. After etoposide exposure for up to 24 hours, some nuclear accumulation of p53 was observed in the ER subclone, as analysed by Western blotting. The conformation of p53, however, was not changed from mutated toward wild-type during exposure in either of the subclones as analysed by flow cytometry. In conclusion, etoposide-induced change in cellular redox state was associated with apoptosis, but was not a sufficient stimulus for p53 to make its conformation active. Thus, mutated p53 seems to have no role in etoposide-induced apoptosis.