The effect of aircraft, road, and railway traffic noise on stroke - results of a case-control study based on secondary data.

AIM: To examine the stroke risks associated with aircraft, road traffic, and railway noise exposure in a large case-control study. MATERIALS AND METHODS: All people aged ≥40 years living around the Frankfurt airport that were insured by one of three large statutory health insurance funds between 2005 and 2010 were included in the study (n = 1,026,670). Address-specific exposure to aircraft, road, and railway traffic noise was estimated for 2005. We used insurance claim data to identify 25,495 newly diagnosed cases of stroke between 2006 and 2010 and compared them with 827,601 control participants. Logistic regression analysis was used to calculate the odds ratios adjusted for age, sex, local proportion of people receiving unemployment benefits, and if available individual indicators of socioeconomic status (education, occupation). RESULTS: For 24-h continuous aircraft noise exposure, neither increased risk estimates nor a positive linear exposure-risk relation was found. However, stroke risk was statistically significantly increased by 7% [95% confidence intervals (95%CI): 2-13%] for people who were exposed to <40 dB of 24-h continuous aircraft noise, but ≥6 events of maximum nightly sound pressure levels ≥50 dB. For road and railway traffic noise, there was a positive linear exposure-risk relation: Per 10 dB the stroke risk increased by 1.7% (95%CI: 0.3-3.2%) for road traffic noise and by 1.8% (95%CI: 0.1-3.3%) for railway traffic noise. The maximum risk increase of 7% (95%CI: 0-14%) for road traffic noise and 18% (95%CI: 2-38%) for railway traffic noise was found in the exposure category ≥65 to <70 dB. CONCLUSION: This large case-control study indicates that traffic noise exposure may lead to an increase in stroke risk. It furthermore suggests that maximum aircraft noise levels at night increase the stroke risk even when continuous noise exposure is low, and thus highlights the relevance of maximum noise levels for research and policies on noise protection.

Traffic noise and hypertension - results from a large case-control study.

BACKGROUND: Environmental traffic noise is a potential cause of hypertension. We aimed to study the association between hypertension as recorded in health insurance claims data and the exposure to three sources of traffic noise (aircraft, road and rail). METHODS: This large case-control study was conducted among persons aged 40 and above in 2010 and living in the region around Frankfurt airport in Germany. Individual residential noise exposure for the index year 2005 was assessed using standard noise algorithms. Cases were all newly diagnosed cases of hypertension recorded in three large health insurances databases in the period 2006-2010. Controls had no hypertension diagnosis. Categorical and continuous analyses were conducted with binary logistic regression models adjusted for sex, age and residential area-based socioeconomic information. RESULTS: The main analysis included 137,577 cases and 355,591 controls. There were no associations with any of the traffic noise sources. Odds ratios (OR) per 10dB noise increase were 0.99 (95% confidence interval: 0.98;1.01) for aircraft noise, and 1.00 (0.99;1.01) both for road and railway noise. Similarly, nighttime noise levels showed no associations with hypertension. Odds ratios were increased for the subgroup of newly diagnosed hypertension cases with a subsequent diagnosis of hypertensive heart disease: per 10dB aircraft noise there was a 13.9% OR increase (6.0% for road traffic, 5.4% for rail traffic). Increases were also noted when we analyzed cases with a longer exposure-outcome time window. CONCLUSION: Our results are suggestive of an association of noise exposure with clinically more severe hypertension diagnoses, but not with uncomplicated hypertension. The absence of individual confounder data, however, adds to the risk of bias. The results contribute to evidence on traffic noise as a cardiovascular risk factor.

Association between aircraft, road and railway traffic noise and depression in a large case-control study based on secondary data.

BACKGROUND: Few studies have examined the relationship between traffic noise and depression providing inconclusive results. This large case-control study is the first to assess and directly compare depression risks by aircraft, road traffic and railway noise. METHODS: The study population included individuals aged ≥40 years that were insured by three large statutory health insurance funds and were living in the region of Frankfurt international airport. Address-specific exposure to aircraft, road and railway traffic noise in 2005 was estimated. Based on insurance claims and prescription data, 77,295 cases with a new clinical depression diagnosis between 2006 and 2010 were compared with 578,246 control subjects. RESULTS: For road traffic noise, a linear exposure-risk relationship was found with an odds ratio (OR) of 1.17 (95% CI=1.10-1.25) for 24-h continuous sound levels ≥70dB. For aircraft noise, the risk estimates reached a maximum OR of 1.23 (95% CI=1.19-1.28) at 50-55dB and decreased at higher exposure categories. For railway noise, risk estimates peaked at 60-65dB (OR=1.15, 95% CI=1.08-1.22). The highest OR of 1.42 (95% CI=1.33-1.52) was found for a combined exposure to noise above 50dB from all three sources. CONCLUSIONS: This study indicates that traffic noise exposure might lead to depression. As a potential explanation for the decreasing risks at high traffic noise levels, vulnerable people might actively cope with noise (e.g. insulate or move away).

Development of a mobbing short scale in the Gutenberg Health Study.

PURPOSE: Despite its highly detrimental potential, most standard questionnaires assessing psychosocial stress at work do not include mobbing as a risk factor. In the German standard version of COPSOQ, mobbing is assessed with a single item. In the Gutenberg Health Study, this version was used together with a newly developed short scale based on the Leymann Inventory of Psychological Terror. The purpose of the present study was to evaluate the psychometric properties of these two measures, to compare them and to test their differential impact on relevant outcome parameters. METHODS: This analysis is based on a population-based sample of 1441 employees participating in the Gutenberg Health Study. Exploratory and confirmatory factor analyses and reliability analyses were used to assess the mobbing scale. To determine their predictive validities, multiple linear regression analyses with six outcome parameters and log-binomial regression models for two of the outcome aspects were run. RESULTS: Factor analyses of the five-item scale confirmed a one-factor solution, reliability was α = 0.65. Both the single-item and the five-item scales were associated with all six outcome scales. Effect sizes were similar for both mobbing measures. CONCLUSION: Mobbing is an important risk factor for health-related outcomes. For the purpose of psychosocial risk assessment in the workplace, both the single-item and the five-item constructs were psychometrically appropriate. Associations with outcomes were about equivalent. However, the single item has the advantage of parsimony, whereas the five-item construct depicts several distinct forms of mobbing.

Occupational polycyclic aromatic hydrocarbon exposure and risk of larynx cancer: a systematic review and meta-analysis.

Polycyclic aromatic hydrocarbons (PAH) are genotoxic substances formed during combustion. Occupational PAH exposure has been shown to increase the risk of lung cancer and may be associated with other respiratory cancers. We conducted a systematic review and meta-analysis to clarify the relationship between occupational PAH exposures and larynx malignancies. We searched EMBASE and MEDLINE (until July 2014) using a series of search strings developed to seek case-control studies or longitudinal studies of workers (Population) exposed to PAHs (Exposure) and their risk for larynx cancer incidence and/or mortality (Outcome). Two independent reviewers screened the titles and abstracts for eligible articles and a third reviewer negotiated consensus. Further assessments of eligibility and sources of bias were conducted in a similar manner. The study results were pooled with random effects meta-analysis. The search resulted in 3377 records. The data of 92 full-text articles representing 63 studies were included and extracted. The majority of studies (n=47) was judged likely to be biased; only 16 studies were judged as methodologically adequate. The pooled effect size was 1.45 (95% CI 1.30 to 1.62; I(2)=30.7%; [Formula: see text]=0.03) for larynx cancer incidence and 1.34 (95% CI 1.18 to 1.53; I(2)=23.8%; [Formula: see text]=0.03) for larynx cancer mortality. While few studies allowed an investigation of dose-response, these indicate a positive dose-response effect. Although most studies may underestimate the true effect due to inexact approximations of PAH exposure, the meta-analysis suggests a robust positive association between PAH and larynx cancer.

The Gutenberg Health Study: measuring psychosocial factors at work and predicting health and work-related outcomes with the ERI and the COPSOQ questionnaire.

BACKGROUND: Several instruments have been developed to assess psychosocial workload. We compared two of these instruments, the Effort-Reward Imbalance (ERI) model and the Copenhagen Psychosocial Questionnaire (COPSOQ) with regard to congruent validity and internal validity. METHODS: This analysis is based on a population-based sample of the baseline examination of 2,783 employees from the Gutenberg Health Study (GHS). About half of the participants completed the ERI questionnaire (n = 1,342), the other half completed the COPSOQ (n = 1,441). First, the two samples were compared and descriptive analyses were carried out calculating mean values for both instruments in general, then separately for age, gender and main occupational groups. Second, we analyzed the relationship between ERI and COPSOQ scales on the workplace situation and on the workplace outcomes: job satisfaction, general health, burnout, satisfaction with life, by applying stepwise logistic regression analysis. RESULTS AND DISCUSSION: For the majority of occupations, high effort as reflected by the ERI corresponded with high demands as reflected by the COPSOQ. Comparably, high reward (according to ERI) yielded a good agreement with high "influence and development" (according to COPSOQ). However, we could also find differences between ERI and COPSOQ concerning the intensity of psychosocial workload in some occupations (e.g., physicians/pharmacists or warehouse managers/warehousemen/transport workers). These differences point to differing theoretical concepts of ERI and COPSOQ. When the ability of ERI and COPSOQ was examined to determine the associations with health and work outcomes, burnout could be better predicted by the COPSOQ; this might be due to the fact that COPSOQ comprises the constructs "work-privacy conflict" and "emotional demand", which are closely related to burnout. However, methodological differences between these instruments limit their direct comparability. CONCLUSIONS: The ERI and COPSOQ instrument yielded similar results for most occupational groups. The slightly stronger association between psychosocial workload as assessed by COPSOQ and burnout might be explained by its broader approach. The ability of the ERI and COPSOQ instrument to reflect relevant risk factors for clinically manifest disorders (e.g., coronary heart disease) will be derived from subsequent prospective analyses of the GHS with the follow-up data.

Tissue-specific regulatory network extractor (TS-REX): a database and software resource for the tissue and cell type-specific investigation of transcription factor-gene networks.

The prediction of transcription factor binding sites in genomic sequences is in principle very useful to identify upstream regulatory factors. However, when applying this concept to genomes of multicellular organisms such as mammals, one has to deal with a large number of false positive predictions since many transcription factor genes are only expressed in specific tissues or cell types. We developed TS-REX, a database/software system that supports the analysis of tissue and cell type-specific transcription factor-gene networks based on expressed sequence tag abundance of transcription factor-encoding genes in UniGene EST libraries. The use of expression levels of transcription factor-encoding genes according to hierarchical anatomical classifications covering different tissues and cell types makes it possible to filter out irrelevant binding site predictions and to identify candidates of potential functional importance for further experimental testing. TS-REX covers ESTs from H. sapiens and M. musculus, and allows the characterization of both presence and specificity of transcription factors in user-specified tissues or cell types. The software allows users to interactively visualize transcription factor-gene networks, as well as to export data for further processing. TS-REX was applied to predict regulators of Polycomb group genes in six human tumor tissues and in human embryonic stem cells.

A validation study revealed differences in design and performance of search filters for qualitative research in PsycINFO and CINAHL.

OBJECTIVES: Search filters can support qualitative evidence of information retrieval. Various search filters are available for the bibliographic databases PsycINFO and CINAHL. To date, no comparative overview of validation results of search filters verified with an independent gold standard exists. STUDY DESIGN AND SETTING: Identified search filters for PsycINFO and CINAHL were tested for plausibility. Gold standards were generated according to the relative recall approach using references included in an overview of systematic reviews of qualitative studies. All included references were collected and checked for indexing in PsycINFO and CINAHL. Validation tests for each search filter were conducted in both databases to determine whether the references of the gold standards could be retrieved or not. RESULTS: Twelve search filters for PsycINFO and fifteen for CINAHL were validated. The complexity and design of these search filters vary, as well as the validation results for the databases. When locating primary studies of qualitative research, the best sensitivity and precision ratio (among filters with a sensitivity of >80%) was achieved with a filter by McKibbon et al. for PsycINFO and a filter by Wilczynski et al. for CINAHL. CONCLUSION: Project-specific requirements and resources influence the choice of a specific search filter for PsycINFO and CINAHL.

A validation study revealed differences in design and performance of MEDLINE search filters for qualitative research.

OBJECTIVES: Several search filters exist to identify qualitative research, but so far none of them has been validated with an independent set of relevant references irrespective of a medical topic. The objective of this study was to provide a comparative overview of validation results for various MEDLINE search filters. STUDY DESIGN AND SETTING: Search filters were tested for plausibility. A relative recall approach was used to generate a gold standard based on an overview of systematic reviews of qualitative studies. For each review, the included qualitative studies were collected and checked for MEDLINE-indexing. The body of indexed articles yielded the gold standard. Validation tests were conducted to determine whether the references of the gold standard could be identified with the respective search filters. RESULTS: Thirteen search filters were validated in MEDLINE. One search filter by Wong et al. (2004) was found to be the most sensitive (93.63%). While medical subject heading "qualitative research" achieved the best precision (2.15%), sensitivity was the lowest (22.56%). University of Texas provided the best balanced search filter with a sensitivity of 81.96% and a precision of 0.80%. CONCLUSION: Search filters to identify qualitative research in MEDLINE differ greatly in design and performance. The selection of the appropriate search filter depends on project-specific demands and resources.

Musculoskeletal Complaints in Occupational Therapists Compared to the General Population: A Cross-Sectional Study in Germany.

Occupational therapists (OTs) are exposed to physical factors at work, which can lead to an increased risk of musculoskeletal disorders. Most studies examining musculoskeletal complaints in OT report that the neck, shoulders, and lower back are most often afflicted. The aim of the present study was to examine the impact of work as an OT (focusing on specific work tasks) on specific musculoskeletal complaints compared to the general working population. A cross-sectional study involving a self-administered standardized questionnaire was conducted from January until October 2015 in Germany. In OT and the comparison group, the highest 12-month prevalence of musculoskeletal disorders were observed for the lower back, the neck, and the shoulders. In contrast, elevated prevalence ratios (PR) were found for OT in the thumbs (PR = 2.7; 95% CI = 1.9-3.8), the wrists (PR = 1.4; 95% CI = 1.1-1.8), and the elbows (PR = 1.5; 95% CI = 1.0-2.2). OTs were particularly exposed to high exertion hand activity and several stressful postures at work. In conclusion, OTs seem to be at risk of developing work-related musculoskeletal complaints in the thumbs, wrists, and elbows. Preventive measures should help to reduce the exposures caused by highly repetitive and forceful hand activities.

Transcriptional regulation of human survivin by early growth response (Egr)-1 transcription factor.

Survivin, a member of the inhibitor of apoptosis protein family, is involved in both, inhibition of apoptosis and regulation of cell division. Because of the tumor-specific expression of survivin, the reduction of its expression is an important therapeutic option in the treatment of malignant diseases. Thus, we analyzed the transcriptional regulation of survivin in order to establish survivin as a target gene for new therapeutic approaches. Here, we describe a novel regulatory region within the survivin promoter. After treatment with phorbol 12-myristate-13-acetate, the early growth response (Egr)-1 transcription factor binds to the sequence 5'GAGGGGGCG 3' within the human survivin promoter in vitro and in entire cells. In reporter-gene assays and overexpression experiments, survivin is downregulated following exogenous expression of wildtype Egr-1. Using p53 wildtype and mutated cell lines, we show that Egr-1 negatively regulates survivin expression and sensitizes cell lines to TRAIL-induced apoptosis.

Epigenetic and genetic analysis of the survivin promoter in acute myeloid leukemia.

Survivin, an inhibitor of apoptosis (IAP) protein plays a dual role in regulation of mitosis and inhibition of apoptosis. Survivin is expressed in embryonic and fetal organs as well as in most human cancers, but not in normal differentiated adult tissues. In this study we investigated the molecular mechanism involved in overexpression of survivin in acute myeloid leukemia (AML). We used methylation specific PCR (MSP) and bisulfite sequencing to analyze the methylation status of the survivin promoter in primary AML samples and normal peripheral blood mononuclear cells (PBMCs). Both, in patients with de novo AML and normal control samples an unmethylated survivin promoter was present. Mutational analysis of the proximal survivin promoter revealed three single nucleotide polymorphisms (SNPs), where the frequently occurred polymorphism (G/C) at position -31 was detectable in both, AML blasts and healthy PBMCs and showed no significant impact on prognosis in de novo AML patients. These results suggest that the methylation status of the survivin promoter and occurrence of these SNPs within the promoter region of the survivin gene appear to be of minor importance in leukemogenesis.

Breast cancer and exposure to aircraft, road, and railway-noise: a case-control study based on health insurance records.

Objectives Aircraft, road, and rail traffic noise can cause sleep disturbances. Since night work and shorter sleep durations have been linked to increased risks of breast cancer, we examined if 24-hour, or day- or night-time traffic noise exposure may also increase the risk of breast cancer. Methods To investigate the noise-related risks of breast cancer, the pseudonymized insurance records of three large statutory health companies (2005-2010) for women aged ≥40 years living in the region surrounding the Frankfurt international airport were analyzed with address-specific acoustic data representing aircraft, road, and rail-traffic noise. Noise exposure among women with incident breast cancer (N=6643) were compared with that of control subjects (N=471 596) using logistic regression and adjusting for age, hormone replacement therapy, education and occupation (only available for 27.9%), and a regional proportion of persons receiving long-term unemployment benefits as an ecological indicator of socioeconomic level. Analyses were also stratified according to estrogen receptor (ER) status. Results An increased odds ratio (OR) was observed for ER negative (ER-) tumors at 24-hour aircraft noise levels 55-59 dB [OR 55-59 dB 1.41, 95% confidence interval (CI) 1.04-1.90] but not for ER positive (ER+) breast cancers (OR 55-59 dB 0.95, 95% CI 0.75-1.20). Clear associations between road and rail traffic noise were not observed. Conclusions The results indicate increased aircraft noise may be an etiologic factor for ER- breast cancers. However, information regarding potential confounding factors was largely unattainable. Further research is required to understand how environmental noise may be involved in the pathogenesis of ER- breast cancers.

Antisense therapy in clinical oncology: preclinical and clinical experiences.

Nucleic acid molecules have emerged as versatile tools with promising utility as therapeutics for human diseases. The specificity of hybridization of an antisense oligonucleotide (AS ODN) to the target mRNA makes the AS strategy attractive to selectively modulate the expression of genes involved in the pathogenesis of malignant or non-malignant diseases. One AS drug has been approved for local therapy of cytomegalovirus retinitis, and a number of AS ODN are currently tested in clinical trials including ODN that target bcl-2, survivin, and DNA methyltransferase. The clinical studies indicate that AS ODN are well tolerated and may have therapeutic activity. In this overview, we summarize therapeutic concepts, clinical studies, and new promising molecular targets to treat human cancer with AS ODN.

Myocardial Infarction Risk Due to Aircraft, Road, and Rail Traffic Noise.

BACKGROUND: Traffic noise can induce stress reactions that have effects on the cardiovascular system. The exposure-risk relationship between aircraft, road, and rail traffic noise and myocardial infarction is currently unknown. METHODS: 19 632 patients from the Rhine-Main region of Germany who were diagnosed with myocardial infarction in the years 2006-2010 were compared with 834 734 control subjects. The assignment of persons to groups was performed on the basis of billing and prescription data from three statutory health insurance carriers. The exposure of all insurees to aircraft, road, and rail traffic noise in 2005 was determined from their residence addresses. As estimators of risk, odds ratios (OR) were calculated by logistic regression analysis, with adjustment for age, sex, regional social status variables, and individual social status (if available). The evaluation was performed on the basis of the continuous 24-hour noise level and the categorized noise level (in 5 decibel classes). RESULTS: The linear model revealed a statistically significant risk increase due to road noise (2.8% per 10 dB rise, 95% confidence interval [1.2; 4.5]) and railroad noise (2.3% per 10 dB rise [0.5; 4.2]), but not airplane noise. Airplane noise levels of 60 dB and above were associated with a higher risk of myocardial infarction (OR 1.42 [0.62; 3.25]). This higher risk is statistically significant if the analysis is restricted to patients who had died of myocardial infarction by 2014/2015 (OR 2.70 [1.08; 6.74]. In this subgroup, the risk estimators for all three types of traffic noise were of comparable magnitude (3.2% to 3.9% per 10 dB rise in noise level). CONCLUSION: In this study, a substantial proportion of the population was exposed to traffic noise levels that were associated with an albeit small increase in the risk of myocardial infarction. These findings underscore the importance of effective traffic noise prevention.

Aircraft, road and railway traffic noise as risk factors for heart failure and hypertensive heart disease-A case-control study based on secondary data.

BACKGROUND: Several studies point to an elevated risk for cardiovascular diseases induced by traffic noise. AIMS: We examined the association between aircraft, road traffic and railway noise and heart failure or hypertensive heart disease (HHD) in a large case-control study. METHODS: The study population consisted of individuals that were insured by three large statutory health insurance funds in the Rhine-Main area of Germany. Based on insurance claims and prescription data, 104,145 cases of heart failure or HHD diagnosed 2006-10 were identified and compared with 654,172 control subjects. Address-specific exposure to aircraft, road and railway traffic noise in 2005 was estimated. Odds Ratios were calculated using logistic regression analysis, adjusted for age, sex, local proportion of persons receiving unemployment benefits, and individual socioeconomic status (available for 39% of the individuals). RESULTS: A statistically significant linear exposure-risk relationship with heart failure or hypertensive heart disease was found for aircraft traffic noise (1.6% risk increase per 10dB increase in the 24-h continuous noise level; 95% CI 0.3-3.0%), road traffic noise (2.4% per 10dB; 95% CI 1.6-3.2%), and railway noise (3.1% per 10dB; 95% CI 2.2-4.1%). For individuals with 24-h continuous aircraft noise levels <40dB and nightly maximum aircraft noise levels exceeding 50dB six or more times, a significantly increased risk was observed. In general, risks of HHD were considerably higher than the risks of heart failure. CONCLUSIONS: Regarding the high prevalence of traffic noise from various sources, even low risk increases for frequent diseases are relevant for the population as a whole.

Decitabine activates specific caspases downstream of p73 in myeloid leukemia.

The demethylating effect of 5-aza-2' deoxycytidine (decitabine, DAC) has been well characterized. The molecular events downstream of methylation inhibition are less well known. Here, DAC was shown to induce apoptosis in acute myeloid leukemia (AML) cells (p53 mutant and wild type) but not in epithelial or normal peripheral blood mononuclear cells. Apoptosis was characterized by activation of the mitochondrial but not the receptor death pathway, as demonstrated by the release of cytochrome c and loss of mitochondrial membrane potential. Western blotting and enzyme assays showed that caspase-3, but not caspase-6 or caspase-8, were activated. Decitabine induced expression of the cell cycle inhibitor p21, arresting AML cell lines in G1 of the cell cycle. Expression of p21 was induced irrespective of the methylation status of its promoter, mediated instead via reexpression of the tumor suppressor p73, an upstream regulator of p21. The promoter of p73 was hypermethylated in AML cell lines in vitro and in primary AML cells ex vivo but not in DAC-resistant epithelial cells. In conclusion, DAC acts on leukemic myeloid cells via caspase activation, which may be dependent on demethylation of the hypermethylated p73 promoter and consequent reexpression of p73.

In vivo expression of survivin and its splice variant survivin-2B: impact on clinical outcome in acute myeloid leukemia.

Survivin, a member of the inhibitor of apoptosis protein family, is expressed in most human cancers, but undetectable in normal differentiated adult tissue in vivo. Because of this cancer-related expression, survivin is a promising target for cancer therapy. To determine the expression and prognostic role of survivin in acute myeloid leukemia (AML), we investigated the mRNA expression pattern of survivin and of the splice variants survivin-2B and survivin-DeltaEx3 in adult (n = 74) and children (n = 31) with de novo AML using RT-PCR. Survivin was the predominant transcript variant in AML cells, whereas significantly lower levels of survivin-2B and survivin-DeltaEx3 were observed (p < or = 0.0001). Neither expression of survivin nor of any splice variant correlated with maturation stage (FAB subtypes, immunophenotype) or cytogenetic risk groups. For AML cases treated according to AMLCG92 (adult) and AML-BFM93 (children) protocols, respectively, expression patterns were correlated with clinical data: in adult AML (n = 51), low expression of survivin-2B correlated with a better overall survival (p = 0.05; mean survival time 19 months vs. 9 months) and a better eventfree survival (p < or = 0.01; 27 months vs. 10 months). In childhood AML (n = 31), high survivin-DeltaEx3 expression was associated with a shorter overall survival (p < or = 0.05; 24 months vs. 43 months). We conclude that certain survivin splice variants have potential prognostic impact for long-term therapy outcome in adult as well as childhood de novo AML.

5-Aza-2'-deoxycytidine induces p21WAF expression by demethylation of p73 leading to p53-independent apoptosis in myeloid leukemia.

The DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR) has significant therapeutic value for the treatment of patients with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). The demethylating effect of 5-Aza-CdR has been well characterized. In contrast, less is known about the molecular events downstream of the methylation inhibition. Here, 5-Aza-CdR induced apoptosis in AML cells (both p53 mutant and wild-type) but not in epithelial or normal PBMCs. Cell death was accompanied by activation of the mitochondrial apoptosis pathway, as shown by release of cytochrome c and AIF and loss of mitochondrial membrane potential (DeltaPsim). Activation of caspase-3 (but not -6 and -8) was detectable using Western blot analysis and measurement of caspase enzymatic activity. 5-Aza-CdR treatment resulted in the induction of p21, which correlated with the arrest of AML cells in the G1 cell cycle phase. Induction of p21 expression was independent of its promoter methylation status but mediated by 5-Aza-CdR-induced reexpression of the tumor-suppressor p73, a known upstream regulator of p21. The p73 promoter was hypermethylated in AML cell lines and in primary AML cells but not in epithelial cells, which were resistant toward 5-Aza-CdR. Therefore, 5-Aza-CdR-mediated specific killing of myeloid cells might be dependent on its ability to revert p73 promoter methylation and to reexpress p73 mRNA. In addition, exogenous expression of p73 rendered epithelial cells sensitive to apoptosis induced by 5-Aza-CdR or other cytostatic drugs. We therefore conclude that p73 is a relevant target for methylation-dependent efficacy of 5-Aza-CdR in AML cells.