Genomic characterization of thymic epithelial tumors in a real-world dataset.

BACKGROUND: Thymic epithelial tumors (TETs) are rare neoplasms arising in the mediastinum, including thymic carcinomas and thymomas. Due to their rarity, little is known about the genomic profiles of TETs. Herein, we investigated the genomic characteristics of TETs evaluated in a large comprehensive genomic profiling database in a real-world setting. METHODS: We included data from two different cohorts: Foundation Medicine Inc. (FMI) in the United States and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan. Samples profiled were examined for all classes of alterations in 253 genes targeted across all assays. Tumor mutational burden (TMB) and microsatellite instability (MSI) were also evaluated. RESULTS: A total of 794 patients were collected in our study, including 722 cases from FMI and 72 cases from C-CAT. In the FMI data, CDKN2A (39.9%), TP53 (30.2%) and CDKN2B (24.6%) were frequently altered in thymic carcinoma, versus TP53 (7.8%), DNMT3A (6.8%), and CDKN2A (5.8%) in thymoma. TMB-high (≥10 mutations/Mb) and MSI were present in 7.0% and 2.3% of thymic carcinomas, and 1.6% and 0.3% of thymomas, respectively. Within C-CAT data, CDKN2A (38.5%), TP53 (36.5%) and CDKN2B (30.8%) were also frequently altered in thymic carcinoma, while alterations of TSC1, SETD2 and LTK (20.0% each) were found in thymoma. CONCLUSIONS: To the best of our knowledge, this is the largest cohort in which genomic alterations, TMB and MSI status of TETs were investigated. Potential targets for treatment previously unbeknownst in TETs are identified in this study, entailing newfound opportunities to advance therapeutic development.

Multipole polaron in the devil's staircase of CeSb.

Rare-earth intermetallic compounds exhibit rich phenomena induced by the interplay between localized f orbitals and conduction electrons. However, since the energy scale of the crystal-electric-field splitting is only a few millielectronvolts, the nature of the mobile electrons accompanied by collective crystal-electric-field excitations has not been unveiled. Here, we examine the low-energy electronic structures of CeSb through the anomalous magnetostructural transitions below the Néel temperature, ~17 K, termed the 'devil's staircase', using laser angle-resolved photoemission, Raman and neutron scattering spectroscopies. We report another type of electron-boson coupling between mobile electrons and quadrupole crystal-electric-field excitations of the 4f orbitals, which renormalizes the Sb 5p band prominently, yielding a kink at a very low energy (~7 meV). This coupling strength is strong and exhibits anomalous step-like enhancement during the devil's staircase transition, unveiling a new type of quasiparticle, named the 'multipole polaron', comprising a mobile electron dressed with a cloud of the quadrupole crystal-electric-field polarization.

Ultraconserved region-containing Transformer 2ß4 controls senescence of colon cancer cells.

Ultraconserved regions (UCRs) are >200 bp genomic segments with perfect human-to-rodent sequence identity. Transcribed UCRs constitute a new category of noncoding RNAs whose functions remain poorly understood. The human transformer 2ß (TRA2B) gene contains a 419-bp UCR spanning the 276-bp exon 2 and its neighboring introns. TRA2B exon 2 has premature stop codons, whereas an exon 2-containing splice variant (TRA2ß4) was expressed preferentially in the nuclei of human colon cancer cells. TRA2ß4 knockdown p53-independently stimulated CDKN1A transcription and increased p21, resulting in the appearance of senescent cells. Biotin pull-down and RNA immunoprecipitation assays revealed that TRA2ß4 interacted with Sp1 through a Sp1-binding sequence (485-GGGG-488) in a stem-loop structure of exon 2. Mutation of this sequence (485-AAGG-488) disrupted the stem-loop structure, blocked the interaction with Sp1 and increased CDKN1A transcription. Overexpression of TRA2ß4 significantly decreased CDKN1A mRNA levels and accelerated cell growth, but the introduction of the mutation in the Sp1-binding sequence completely canceled these effects. Taken together, TRA2ß4 may sequester Sp1 from occupying promoters of target genes including CDKN1A, promoting cell growth by interrupting the senescence-related gene expression program. This novel function of TRA2ß4 may uncover an oncogenic function of transcribed UCRs.

Epidemic myalgia and myositis associated with human parechovirus type 3 infections occur not only in adults but also in children: findings in Yamagata, Japan, 2014.

We previously reported an association between human parechovirus type 3 (HPeV3) and epidemic myalgia with myositis in adults during summers in which an HPeV3 outbreak occurred in children. However, this disease association has not yet been reported elsewhere. We have since continued our surveillance to accumulate data on this disease association and to confirm whether myalgia occurs in children as well as adults. Between June and August 2014, we collected 380 specimens from children with infectious diseases. We also collected clinical specimens from two adult and three paediatric patients suspected of myalgia. We then performed virus isolation and reverse-transcription-PCR using the collected specimens. We detected HPeV3 in 26 children with infectious diseases, which we regarded as indicating an outbreak. We also confirmed HPeV3 infection in all patients suspected of myalgia. In particular the symptoms in two boys, complaining of myalgia and fever, closely matched the criteria for adult myalgia. Based on our findings from 2008, 2011 and 2014, we again urge that clinical consideration be given to the relationship between myalgia and HPeV3 infections during HPeV3 outbreaks in children. Furthermore, our observations from 2014 suggest that epidemic myalgia and myositis occur not only in adults but also in children.

Homeodomain-interacting protein kinase 2 regulates DNA damage response through interacting with heterochromatin protein 1γ.

Homeodomain-interacting protein kinase 2 (HIPK2) is a potential tumor suppressor that has a crucial role in the DNA damage response (DDR) by regulating cell-cycle checkpoint activation and apoptosis. However, it is unclear whether HIPK2 exerts distinct roles in DNA damage repair. The aim of this study was to identify novel target molecule(s) of HIPK2, which mediates HIPK2-dependent DNA damage repair. HIPK2-knockdown human colon cancer cells (HCT116) or hipk1/hipk2 double-deficient mouse embryonic fibroblasts could not remove histone H2A.X phosphorylated at Ser139 (γH2A.X) after irradiation with a sublethal dose (10 J/m(2)) of ultraviolet (UV)-C, resulting in apoptosis. Knockdown of HIPK2 in p53-null HCT116 cells similarly promoted the UV-C-induced γH2A.X accumulation and apoptosis. Proteomic analysis of HIPK2-associated proteins using liquid chromatography-tandem mass spectrometry identified heterochromatin protein 1γ (HP1γ) as a novel target for HIPK2. Immunoprecipitation experiments with HCT116 cells expressing FLAG-tagged HIPK2 and one of the HA-tagged HP1 family members demonstrated that HIPK2 specifically associated with HP1γ, but not with HP1α or HP1ß, through its chromo-shadow domain. Mutation of the HP1box motif (883-PTVSV-887) within HIPK2 abolished the association. HP1γ knockdown also enhanced accumulation of γH2A.X and apoptosis after sublethal UV-C irradiation. In vitro kinase assay demonstrated an HP1γ-phosphorylating activity of HIPK2. Sublethal UV-C irradiation phosphorylated HP1γ. This phosphorylation was absent in endogenous HIPK2-silenced cells with HIPK2 3'UTR siRNA. Overexpression of FLAG-HIPK2, but not the HP1box-mutated or kinase-dead HIPK2 mutant, in the HIPK2-silenced cells increased HP1γ binding to trimethylated (Lys9) histone H3 (H3K9me3), rescued the UV-C-induced phosphorylation of HP1γ, triggered release of HP1γ from histone H3K9me3 and suppressed γH2A.X accumulation. Our results suggest that HIPK2-dependent phosphorylation of HP1γ may participate in the regulation of dynamic interaction between HP1γ and histone H3K9me3 to promote DNA damage repair. This HIPK2/HP1γ pathway may uncover a new functional aspect of HIPK2 as a tumor suppressor.

Downregulation of serine/arginine-rich splicing factor 3 induces G1 cell cycle arrest and apoptosis in colon cancer cells.

Serine/arginine-rich splicing factor 3 (SRSF3) likely has wide-ranging roles in gene expression and facilitation of tumor cell growth. SRSF3 knockdown induced G1 arrest and apoptosis in colon cancer cells (HCT116) in association with altered expression of 833 genes. Pathway analysis revealed 'G1/S Checkpoint Regulation' as the most highly enriched category in the affected genes. SRSF3 knockdown did not induce p53 or stimulate phosphorylation of p53 or histone H2A.X in wild-type HCT116 cells. Furthermore, the knockdown induced G1 arrest in p53-null HCT116 cells, suggesting that p53-dependent DNA damage responses did not mediate the G1 arrest. Real-time reverse transcription-polymerase chain reaction and western blotting confirmed that SRSF3 knockdown reduced mRNA and protein levels of cyclins (D1, D3 and E1), E2F1 and E2F7. The decreased expression of cyclin D and E2F1 likely impaired the G1-to-S-phase progression. Consequently, retinoblastoma protein remained hypophosphorylated in SRSF3 knockdown cells. The knockdown also induced apoptosis in association with reduction of BCL2 protein levels. We also found that SRSF3 knockdown facilitated skipping of 81 5'-nucleotides (27 amino acids) from exon 8 of homeodomain-interacting protein kinase-2 (HIPK2) and produced a HIPK2 Δe8 isoform. Full-length HIPK2 (HIPK2 FL) is constantly degraded through association with an E3 ubiquitin ligase (Siah-1), whereas HIPK2 Δe8, lacking the 27 amino acids, lost Siah-1-binding ability and became resistant to proteasome digestion. Interestingly, selective knockdown of HIPK2 FL induced apoptosis in various colon cancer cells expressing wild-type or mutated p53. Thus, these findings disclose an important role of SRSF3 in the regulation of the G1-to-S-phase progression and alternative splicing of HIPK2 in tumor growth.

Regulation of type 1 IP3 receptor expression by dopamine D2-like receptors via AP-1 and NFATc4 activation.

Type 1 inositol 1,4,5-trisphosphate receptors (IP3Rs-1), together with ryanodine receptors, are major calcium channels to regulate intracellular Ca²âº concentration. Although our recent report demonstrates the essential involvement of IP3R-1 up-regulation induced by dopamine D1-like and D2-like receptor (D1 and D2R) stimulation in psychological dependence, exact regulatory mechanisms of IP3R-1 expression by D2Rs have not yet been clarified. Mouse cerebral cortical neurons were treated with inhibitor of Ca²âº-related signal transduction pathways coupling to D2Rs and used to analyze the mechanisms of IP3R-1 expression regulated by transcriptional factor. A selective D2R agonist, quinpirole, up-regulated IP3R-1 protein following its mRNA increase, which was significantly inhibited by gallein (a Gßγ modulator), U73122 (a phospholipase C inhibitor), BAPTA-AM (an intracellular calcium chelating reagent), W7 (a calmodulin inhibitor), KN-93 (a calmodulin-dependent protein kinases inhibitor), and FK506 (a calcineurin inhibitor). Immunocytochemical assessment showed that quinpirole increased expression of both cFos and phosphorylated-cJun in nucleus and enhanced translocation of NFATc4 complex to nucleus from cytoplasm. In addition, quinpirole directly recruited bindings between AP-1 and IP3R-1 promoter region and between NFATc4 and IP3R-1 promoter region. These results indicate that D2Rs enhance IP3R-1 gene transcription via increased bindings of AP-1 and NFATc4 to IP3R-1 promoter region after Gßγ activation.

Possible involvement of type 1 inositol 1,4,5-trisphosphate receptors up-regulated by dopamine D1 and D2 receptors in mouse nucleus accumbens neurons in the development of methamphetamine-induced place preference.

Little is known about regulatory mechanisms of type 1 inositol-1,4,5-triphosphate receptor (IP(3)R-1) expression in conditioned place preference by methamphetamine (METH), though significant enhancement of IP(3)R-1 expression in the mouse frontal cortex and limbic forebrain by intermittent administration of cocaine is reported. The present study investigated the role and regulation of IP(3)R-1 in mice with METH-induced place preference. Injection of IP(3)R antagonists with different chemical structures, 2-aminophenoxyethane-borate and xestospongin C, into the mouse nucleus accumbens (NAcc) dose-dependently inhibited METH-induced place preference. The levels of IP(3)R-1 protein in the NAcc of METH-conditioned mice significantly increased, which was completely abolished by microinjection of SCH23390 and raclopride, selective dopamine D1-like and D2-like receptor (D1 and D2DR) antagonists respectively, into the mouse NAcc. Immunohistochemical assessment revealed co-localization of immunoreactivity for IP(3)R-1 and those for D1 and D2DRs in the NAcc. These findings suggest that IP(3)R-1 could be involved in the development of METH-induced place preference and that D1 and D2DRs in the NAcc of mice showing METH-induced place preference play possible regulatory roles in IP(3)R-1 expression.

Formation of high heat resistant coatings by using gas tunnel type plasma spraying.

UNLABELLED: Zirconia sprayed coatings are widely used as thermal barrier coatings (TBC) for high temperature protection of metallic structures. However, their use in diesel engine combustion chamber components has the long run durability problems, such as the spallation at the interface between the coating and substrate due to the interface oxidation. Although zirconia coatings have been used in many applications, the interface spallation problem is still waiting to be solved under the critical conditions such as high temperature and high corrosion environment. The gas tunnel type plasma spraying developed by the author can make high quality ceramic coatings such as Al2O3 and ZrO2 coating compared to other plasma spraying method. A high hardness ceramic coating such as Al2O3 coating by the gas tunnel type plasma spraying, were investigated in the previous study. The Vickers hardness of the zirconia (ZrO2) coating increased with decreasing spraying distance, and a higher Vickers hardness of about Hv = 1200 could be obtained at a shorter spraying distance of L = 30 mm. ZrO2 coating formed has a high hardness layer at the surface side, which shows the graded functionality of hardness. In this study, ZrO2 composite coatings (TBCs) with Al2O3 were deposited on SS304 substrates by gas tunnel type plasma spraying. The performance such as the mechanical properties, thermal behavior and high temperature oxidation resistance of the functionally graded TBCs was investigated and discussed. The resultant coating samples with different spraying powders and thickness are compared in their corrosion resistance with coating thickness as variables. Corrosion potential was measured and analyzed corresponding to the microstructure of the coatings. KEYWORDS: High Heat Resistant Coatings, Gas Tunnel Type Plasma Spraying, Hardness,

International models of investigator-initiated trials: implications for Japan.

BACKGROUND: Academic/institutional investigator-initiated clinical trials benefit individuals and society by supplementing gaps in industry-sponsored clinical trials. MATERIALS: In May 2010, experts from Japan, the Republic of Korea, the UK, and the United States, met at a symposium in Tokyo, Japan, to discuss how policies related to the conduct of clinical trials, which have been shown to be effective, may be applied to other regions of the world. RESULTS: In order to increase the availability of anticancer drugs world-wide, nations including Japan should examine the benefits of increasing the number of investigator-initiated clinical trials. These trials represent one of the most effective ways to translate basic scientific knowledge into clinical practice. These trials should be conducted under GCP guidelines and include Investigational New Drug application submissions with the ultimate goal of future drug approval. CONCLUSIONS: To maximize the effectiveness of these trials, a policy to educate health care professionals, cancer patients and their families, and the public in general on the benefits of clinical trials should be strengthened. Finally, policies that expedite the clinical development of novel cancer drugs which have already been shown to be effective in other countries are needed in many nations including Japan to accelerate drug approval.

Gabapentin blocks methamphetamine-induced sensitization and conditioned place preference via inhibition of α2/δ-1 subunits of the voltage-gated calcium channels.

Our previous investigation demonstrated that repeated administration of morphine significantly enhanced α(2)/δ-1 subunit expression in the frontal cortex and limbic forebrain of mice as well as morphine-induced place preference. However, little is known about regulatory mechanisms of α(2)/δ-1 subunit expression in conditioned place preference by methamphetamine (METH). In the present study, we investigated the role of α(2)/δ-1 subunit of voltage-gated calcium channels (VGCCs) in the mouse brain under repeated treatment with METH. The level of α(2)/δ-1 subunit increased significantly in the limbic forebrain including the nucleus accumbens and the frontal cortex of mice showing METH-induced sensitization. Under these conditions, the development of behavioral sensitization induced by the intermittent administration of METH was significantly suppressed by the co-administration of gabapentin (GBP) with binding activity to an exofacial epitope of α(2)/δ-1 subunit. Furthermore, GBP administered i.c.v. caused a dose-dependent inhibition of the METH-induced place preference. Chronic GBP treatment at the dose alleviating sensitization and place preference significantly reduced the elevation of α(2)/δ-1 subunit of VGCC induced by the repeated administration of METH in the limbic forebrain and frontal cortex, whereas there were no changes in the increase of α(2)/δ-1 subunit mRNA. These findings indicate that α(2)/δ-1 subunit plays a critical role in the development of METH-induced place preference following neuronal plasticity, and that GBP, which significantly suppressed METH-induced place preference by its possible inhibitory action of α(2)/δ subunit to neuronal membrane, may possibly be used as an alternative drug to treat or prevent drug dependence.

Microstructure and thermal behaviour of plasma sprayed zirconia/alumina composite coating.

In thermal barrier coatings (TBC), failure occurs near or at the interface between the metallic bondcoat and topcoat. On high temperature conditions, an oxide scale which is named thermally grown oxide (TGO) occurs along the bond/topcoat interface. For diminishing the creation of TGO, a dense coating with low residual stress and thermal stress buffer layer was preferable. High hardness ceramic coatings could be obtained by gas tunnel type plasma spraying, and the deposited coating had superior property in comparison with those deposited by conventional type plasma spray method. In this study, the gas tunnel type plasma spraying system was utilized to produce a zirconia/alumina functionally graded thermal barrier coating and discussed its physical and mechanical properties, thermal behavior and high temperature oxidation resistance of the coating are discussed. Consequently, the proposed system exhibited superior mechanical properties and oxidation resistance at the expenses of a slightly lower thermal insulating effect. This interlayer is preferred in order to minimize the detrimental effect of the phase transformation of gamma-Al2O3 to alpha-Al2O3.

Low health-related quality of life is associated with all-cause mortality in patients with diabetes on haemodialysis: the Japan Dialysis Outcomes and Practice Pattern Study.

AIMS: Whether health-related quality of life (HRQoL) can be accurately predicted in patients with extremely low HRQoL as a result of diabetic complications is unclear. We investigated the impact of HRQoL on mortality risk in patients with diabetes on haemodialysis. METHODS: Data from the Dialysis Outcomes Practice Pattern Study (DOPPS) were analysed for randomly selected patients receiving haemodialysis in Japan. Information regarding the diagnosis of diabetes and clinical events during follow-up was abstracted from the medical records at baseline and HRQoL was assessed by a self-reported short form (SF)-36 questionnaire. The association between physical component score and mental component score in the SF-36 and mortality risk was analysed using a Cox proportional hazard model. RESULTS: Data from 527 patients with diabetes on haemodialysis were analysed. The mortality age-adjusted hazard ratio of having a physical component score greater than or equal to the median was 0.27 [95% confidence interval (CI) 0.08-0.96] and the multivariable-adjusted mortality hazard ratio of having an mental component score greater than or equal to the median was 1.21 (95% CI 0.44-3.35). CONCLUSIONS: The physical component score derived from the SF-36 is an independent risk factor for mortality in patients with diabetes on haemodialysis who generally had very low HRQoL scores. Baseline mental component score was not predictive of mortality. Patient self-reporting regarding the physical component of health status may aid in risk stratification and clinical decision making for patients with diabetes on haemodialysis.

Role of alpha2/delta subunit in the development of morphine-induced rewarding effect and behavioral sensitization.

Previous data demonstrate that L-type voltage-gated calcium channel (VGCC) blockers, which bind to alpha(1) subunits of VGCC to suppress Ca(2+) entry into cells, inhibit the development of psychological dependence on drugs of abuse, suggesting the upregulation of L-type VGCC in the development of psychological dependence. However, there are few available data on changes of the auxiliary subunit alpha(2)/delta modifying L-type VGCC under such conditions. We therefore investigated here the role of alpha(2)/delta subunits of VGCCs in the brain of mouse after repeated treatment with morphine. The treatment with morphine increased alpha(2)/delta subunit expression in the frontal cortex and the limbic forebrain of mice showing rewarding effect and sensitization to hyperlocomotion by morphine. The morphine-induced behavioral sensitization and place preference were also suppressed by gabapentin, which binds to an exofacial epitope of the alpha(2)/delta auxiliary subunits of VGCCs. These findings indicate that the upregulation of alpha(2)/delta subunit as well as alpha(1) subunits of VGCC in the frontal cortex and the limbic forebrain plays a critical role in development of morphine-induced rewarding effect and behavioral sensitization following neuronal plasticity.

Depressive symptoms predict the future risk of severe pruritus in haemodialysis patients: Japan Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Recent reports suggest a cross-sectional association between psychiatric distress and pruritus in patients on haemodialysis (HD). However, no study has examined the likelihood of developing severe pruritus in patients on HD with depressive symptoms. OBJECTIVES: To evaluate the relationship between baseline depressive symptoms and subsequent risk of developing severe pruritus. METHODS: A longitudinal study with a 0.5-2.5-year follow-up period was performed using 1799 patients on HD who had no/mild pruritus at baseline, based on the Japan Dialysis Outcomes and Practice Patterns Study (1996-2004), a cohort study composed of a representative sample of patients on HD. We assessed pruritus after the follow-up period using a self-reported questionnaire and depressive symptoms using scores from the five-item version of the Mental Health Inventory (MHI-5). RESULTS: The 1799 patients had a mean age of 56.9 years, 59.5% were men, and 23.6% presented depressive symptoms. Multivariable analysis revealed that patients with depressive symptoms had significantly higher odds of developing severe pruritus during the 0.5-2.5-year follow-up period [adjusted odds ratio (AOR) 1.57, 95% confidence interval 1.22-2.01, P < 0.001]. In addition, a significant linear trend was observed between baseline MHI-5 scores and risk of developing severe pruritus, with AORs for third, second and first MHI-5 score quartiles of 1.08, 1.51 and 1.95, respectively (P for trend < 0.0001). CONCLUSIONS: Our results suggest that depressive symptoms measured by MHI-5 may predict the future risk of developing severe pruritus in patients on HD.

Muscular fatigue and decremental response to repetitive nerve stimulation in X-linked spinobulbar muscular atrophy.

BACKGROUND AND PURPOSE: We report decremental responses to repetitive nerve stimulation (RNS) in 11 patients diagnosed with X-linked spinobulbar muscular atrophy (X-SBMA). METHODS: The compound muscle action potential (CMAP) of the right abductor digiti minimi (ADM) and trapezius (TZ) in response to a 3-Hz stimulation of the ulnar nerve at the wrist and accessory nerve at the neck were recorded by surface electrodes. RESULTS: A decremental response to RNS was observed in 90.9% of the TZ muscle and 27.2% in the ADM muscle of patients with X-SBMA. CONCLUSION: These electrophysiological features of X-SBMA are considered to be useful for diagnosis of X-SBMA. Furthermore, the waning phenomena that mostly appeared in the TZ muscle and increment of CMAP in RNS after the exercise also suggest a unique manifestation in X-SBMA.

Treatment of a citrin-deficient patient at the early stage of adult-onset type II citrullinaemia with arginine and sodium pyruvate.

Citrin deficiency is a common congenital metabolic defect not only in East Asian populations but also in other populations around the world. It has been shown that although liver transplantation is ultimately required in many patients to prevent neurological decompensation associated with hyperammonaemia, arginine is effective in lowering ammonia in hyperammonaemic patients, and a high-protein low-carbohydrate diet may provide some benefit to infants in improving failure to thrive. In the present study, the clinical symptoms and laboratory findings are reported for a 13-year-old citrin-deficient girl in the early stage of adult-onset type II citrullinaemia (CTLN2), and the therapeutic effect of orally administered arginine and sodium pyruvate was investigated. The patient complained of anorexia, lethargy, fatigue and poor growth, and showed laboratory findings typical of CTLN2; elevated levels of plasma citrulline, threonine-to-serine ratio, and serum pancreatic secretory trypsin inhibitor. Oral administration of arginine and sodium pyruvate for over 3 years improved her clinical symptoms and has almost completely normalized her laboratory findings. It is suggested that the administration of arginine and sodium pyruvate with low-carbohydrate meals may be an effective therapy in patients with citrin deficiency in order either to prolong metabolic normalcy or to provide a safer and more affordable alternative to liver transplantation.

Diabetes, glycaemic control and mortality risk in patients on haemodialysis: the Japan Dialysis Outcomes and Practice Pattern Study.

AIMS/HYPOTHESIS: There are few data on the target level of glycaemic control among patients with diabetes on haemodialysis. We investigated the impact of glycaemic control on mortality risk among diabetic patients on haemodialysis. SUBJECTS AND METHODS: Data were analysed from the Dialysis Outcomes Practice Pattern Study (DOPPS) for randomly selected patients on haemodialysis in Japan. The diagnosis of diabetes at baseline and information on clinical events during follow-up were abstracted from the medical records. A Cox proportional hazards model was used to evaluate the association between presence or absence of diabetes, glycaemic control (HbA(1c) quintiles) and mortality risk. RESULTS: Data from 1,569 patients with and 3,342 patients without diabetes on haemodialysis were analysed. Among patients on haemodialysis, those with diabetes had a higher mortality risk than those without (multivariable hazard ratio 1.37, 95% CI 1.08-1.74). Compared with those in the bottom quintile of HbA(1c) level, the multivariable-adjusted hazard ratio for mortality was not increased in the bottom second to fourth quintiles of HbA(1c) (HbA(1c) 5.0-5.5% to 6.2-7.2%), but was significantly increased to 2.36 (95% CI 1.02-5.47) in the fifth quintile (HbA(1c) > or = 7.3%). The effect of poor glycaemic control did not statistically correlate with baseline mortality risk (p = 0.27). CONCLUSIONS/INTERPRETATION: Among dialysis patients, poorer glycaemic control in those with diabetes was associated with higher mortality risk. This suggests a strong effect of poor glycaemic control above an HbA(1c) level of about 7.3% on mortality risk, and that this effect does not appear to be influenced by baseline comorbidity status.