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Find video protocols related to scientific articles indexed in Pubmed.
Hmga2 is a direct target gene of RUNX1 and regulates expansion of myeloid progenitors in mice.
Blood
PUBLISHED: 08-22-2014
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RUNX1 is a master transcription factor in hematopoiesis and mediates the specification and homeostasis of hematopoietic stem and progenitor cells (HSPCs). Disruptions in RUNX1 are well known to lead to hematologic disease. In this study, we sought to identify and characterize RUNX1 target genes in HSPCs by performing RUNX1 chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) using a murine HSPC line and complementing this data with our previously described gene expression profiling of primary wild-type and RUNX1-deficient HSPCs (Lineage(-)/cKit(+)/Sca1(+)). From this analysis, we identified and confirmed that Hmga2, a known oncogene, as a direct target of RUNX1. Hmga2 was strongly upregulated in RUNX1-deficient HSPCs, and the promoter of Hmga2 was responsive in a cell-type dependent manner upon coexpression of RUNX1. Conditional Runx1 knockout mice exhibit expansion of their HSPCs and myeloid progenitors as hallmark phenotypes. To further validate and establish that Hmga2 plays a role in inducing HSPC expansion, we generated mouse models of HMGA2 and RUNX1 deficiency. Although mice lacking both factors continued to display higher frequencies of HSPCs, the expansion of myeloid progenitors was effectively rescued. The data presented here establish Hmga2 as a transcriptional target of RUNX1 and a critical regulator of myeloid progenitor expansion.
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Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation.
Nat Commun
PUBLISHED: 05-21-2014
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Loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), are observed in ~\n10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML). Recent studies have shown that EZH2 mutations are often associated with RUNX1 mutations in MDS patients, although its pathological function remains to be addressed. Here we establish an MDS mouse model by transducing a RUNX1S291fs mutant into hematopoietic stem cells and subsequently deleting Ezh2. Ezh2 loss significantly promotes RUNX1S291fs-induced MDS. Despite their compromised proliferative capacity of RUNX1S291fs/Ezh2-null MDS cells, MDS bone marrow impairs normal hematopoietic cells via selectively activating inflammatory cytokine responses, thereby allowing propagation of MDS clones. In contrast, loss of Ezh2 prevents the transformation of AML via PRC1-mediated repression of Hoxa9. These findings provide a comprehensive picture of how Ezh2 loss collaborates with RUNX1 mutants in the pathogenesis of MDS in both cell autonomous and non-autonomous manners.
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Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP-9 upregulation in leukemic cells.
Blood
PUBLISHED: 05-13-2014
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High levels of HES1 expression are frequently found in BCR-ABL(+) chronic myelogenous leukemia in blast crisis (CML-BC). In mouse bone marrow transplantation (BMT) models, co-expression of BCR-ABL and Hes1 induces CML-BC-like disease; however, the underlying mechanism remained elusive. Here, based on gene expression analysis, we show that MMP-9 is upregulated by Hes1 in common myeloid progenitors (CMPs). Analysis of promoter activity demonstrated that Hes1 upregulated MMP-9 by activating NF-?B. Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of HES1 expression. Interestingly, MMP-9 deficiency impaired the cobblestone area-forming ability of CMPs expressing BCR-ABL and Hes1 that were in conjunction with a stromal cell layer. In addition, CMPs expressing BCR-ABL and Hes1 secreted MMP-9, promoting the release of soluble Kit-ligand (sKitL) from stromal cells, thereby enhancing proliferation of the leukemic cells. In accordance, mice transplanted with CMPs expressing BCR-ABL and Hes1 exhibited high levels of sKitL as well as MMP-9 in the serum. Importantly, MMP-9 deficiency impaired the development of CML-BC-like disease induced by BCR-ABL and Hes1 in mouse BMT models. The present results suggest that Hes1 promotes the development of CML-BC, partly through MMP-9 upregulation in leukemic cells.
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Differences in associations between visceral fat accumulation and obstructive sleep apnea by sex.
Ann Am Thorac Soc
PUBLISHED: 01-30-2014
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The difference in mortality from obstructive sleep apnea (OSA) by sex is an important issue. Visceral fat, a significant risk factor for cardiovascular disease, was reported to be closely related to OSA.
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The additive impact of periodic limb movements during sleep on inflammation in patients with obstructive sleep apnea.
Ann Am Thorac Soc
PUBLISHED: 01-18-2014
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Both periodic limb movements during sleep (PLMS) and obstructive sleep apnea (OSA) are major causes of sleep disorders and have been associated with systemic inflammation and cardiovascular events. However, it is uncertain whether in combination they promote a higher inflammatory response and greater risk of cardiovascular events than each condition alone.
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Obesity hypoventilation syndrome in Japan and independent determinants of arterial carbon dioxide levels.
Respirology
PUBLISHED: 01-15-2014
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Obesity hypoventilation syndrome (OHS) prevalence was previously estimated at 9% in patients with obstructive sleep apnoea (OSA) in Japan. However, the definition of OSA in that study was based on an apnoea-hypopnoea index (AHI) of ? 20/h rather than ? 5/h. Therefore, the prevalence of OHS in OSA was not measured in the same way as for Western countries. Our study objectives were to investigate the characteristics of Japanese patients with OHS.
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Hes1 upregulation contributes to the development of FIP1L1-PDGRA-positive leukemia in blast crisis.
Exp. Hematol.
PUBLISHED: 01-01-2014
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We have previously shown that elevated expression of Hairy enhancer of split 1 (Hes1) contributes to blast crisis transition in Bcr-Abl-positive chronic myelogenous leukemia. Here we investigate whether Hes1 is involved in the development of other myeloid neoplasms. Notably, Hes1 expression was elevated in only a few cases of 65 samples with different types of myeloid neoplasms. Interestingly, elevated expression of Hes1 was found in two of five samples of Fip1-like1 platelet-derived growth factor receptor-? (FIP1L1-PDGFA)-positive myeloid neoplasms associated with eosinophilia. Whereas FIP1L1-PDGFR? alone induced acute T-cell leukemia or myeloproliferative neoplasms in mouse bone marrow transplantation models, mice transplanted with bone marrow cells expressing both Hes1 and FIP1L1-PDGFR? developed acute leukemia characterized by an expansion of myeloid blasts and leukemic cells without eosinophilic granules. FIP1L1-PDGFR? conferred cytokine-independent growth to Hes1-transduced common myeloid progenitors, interleukin-3-dependent cells. Imatinib inhibited the growth of common myeloid progenitors expressing Hes1 with FIP1L1-PDGFR?, but not with imatinib-resistant FIP1L1-PDGFR? mutants harboring T674I or D842V. In contrast, ponatinib efficiently eradicated leukemic cells expressing Hes1 and the imatinib-resistant FLP1L1-PDGFR? mutant in vitro and in vivo. Thus, we have established mouse models of FIP1L1-PDGFRA-positive leukemia in myeloid blast crisis, which will help elucidate the pathogenesis of the disease and develop a new treatment for it.
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Myelodysplastic syndromes are induced by histone methylation-altering ASXL1 mutations.
J. Clin. Invest.
PUBLISHED: 04-29-2013
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Recurrent mutations in the gene encoding additional sex combs-like 1 (ASXL1) are found in various hematologic malignancies and associated with poor prognosis. In particular, ASXL1 mutations are common in patients with hematologic malignancies associated with myelodysplasia, including myelodysplastic syndromes (MDSs), and chronic myelomonocytic leukemia. Although loss-of-function ASXL1 mutations promote myeloid transformation, a large subset of ASXL1 mutations is thought to result in stable truncation of ASXL1. Here we demonstrate that C-terminal-truncating Asxl1 mutations (ASXL1-MTs) inhibited myeloid differentiation and induced MDS-like disease in mice. ASXL1-MT mice displayed features of human-associated MDS, including multi-lineage myelodysplasia, pancytopenia, and occasional progression to overt leukemia. ASXL1-MT resulted in derepression of homeobox A9 (Hoxa9) and microRNA-125a (miR-125a) expression through inhibition of polycomb repressive complex 2-mediated (PRC2-mediated) methylation of histone H3K27. miR-125a reduced expression of C-type lectin domain family 5, member a (Clec5a), which is involved in myeloid differentiation. In addition, HOXA9 expression was high in MDS patients with ASXL1-MT, while CLEC5A expression was generally low. Thus, ASXL1-MT-induced MDS-like disease in mice is associated with derepression of Hoxa9 and miR-125a and with Clec5a dysregulation. Our data provide evidence for an axis of MDS pathogenesis that implicates both ASXL1 mutations and miR-125a as therapeutic targets in MDS.
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RUNX1/AML1 mutant collaborates with BMI1 overexpression in the development of human and murine myelodysplastic syndromes.
Blood
PUBLISHED: 03-07-2013
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RUNX1/AML1 mutations have been identified in myelodysplastic syndromes (MDSs). In a mouse bone marrow transplantation model, a RUNX1 mutant, D171N, was shown to collaborate with Evi1 in the development of MDSs; however, this is rare in humans. Using enforced expression in human CD34(+) cells, we showed that the D171N mutant, the most frequent target of mutation in the RUNX1 gene, had an increased self-renewal capacity, blocked differentiation, dysplasia in all 3 lineages, and tendency for immaturity, but no proliferation ability. BMI1 overexpression was observed in CD34(+) cells from the majority of MDS patients with RUNX1 mutations, but not in D171N-transduced human CD34(+) cells. Cotransduction of D171N and BMI1 demonstrated that BMI1 overexpression conferred proliferation ability to D171N-transduced cells in both human CD34(+) cells and a mouse bone marrow transplantation model. Stepwise transduction of D171N followed by BMI1 in human CD34(+) cells resulted in long-term proliferation with a retained CD34(+) cell fraction, which is quite similar to the phenotype in patients with higher-risk MDSs. Our results indicate that BMI1 overexpression is one of the second hit partner genes of RUNX1 mutations that contribute to the development of MDSs.
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Brazilian green propolis suppresses the hypoxia-induced neuroinflammatory responses by inhibiting NF-?B activation in microglia.
Oxid Med Cell Longev
PUBLISHED: 02-27-2013
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Hypoxia has been recently proposed as a neuroinflammatogen, which drives microglia to produce proinflammatory cytokines, including interleukin-1? (IL-1?), tumor necrosis factor-? (TNF-?), and IL-6. Considering the fact that propolis has hepatoprotective, antitumor, antioxidative, and anti-inflammatory effects, propolis may have protective effects against the hypoxia-induced neuroinflammatory responses. In this study, propolis (50 ?g/mL) was found to significantly inhibit the hypoxia-induced cytotoxicity and the release of proinflammatory cytokines, including IL-1?, TNF-?, and IL-6, by MG6 microglia following hypoxic exposure (1% O2, 24 h). Furthermore, propolis significantly inhibited the hypoxia-induced generation of reactive oxygen species (ROS) from mitochondria and the activation of nuclear factor-?B (NF-?B) in microglia. Moreover, systemic treatment with propolis (8.33 mg/kg, 2 times/day, i.p.) for 7 days significantly suppressed the microglial expression of IL-1?, TNF-?, IL-6, and 8-oxo-deoxyguanosine, a biomarker for oxidative damaged DNA, in the somatosensory cortex of mice subjected to hypoxia exposure (10% O2, 4 h). These observations indicate that propolis suppresses the hypoxia-induced neuroinflammatory responses through inhibition of the NF-?B activation in microglia. Furthermore, increased generation of ROS from the mitochondria is responsible for the NF-?B activation. Therefore, propolis may be beneficial in preventing hypoxia-induced neuroinflammation.
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Flexible positive airway pressure improves treatment adherence compared with auto-adjusting PAP.
Sleep
PUBLISHED: 02-02-2013
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There are no clinical data comparing adherence and quality of life between auto-adjusting positive airway pressure (APAP) and two different flex positive airway pressure (PAP) devices (A-Flex, C-Flex) in patients with obstructive sleep apnea (OSA).
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Association between plasma neutrophil gelatinase associated lipocalin level and obstructive sleep apnea or nocturnal intermittent hypoxia.
PLoS ONE
PUBLISHED: 01-14-2013
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Both obstructive sleep apnea (OSA) and a novel lipocalin, neutrophil gelatinase associated lipocalin (Ngal), have been reported to be closely linked with cardiovascular disease and loss of kidney function through chronic inflammation. However, the relationship between OSA and Ngal has never been investigated.
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Fyn is not essential for Bcr-Abl-induced leukemogenesis in mouse bone marrow transplantation models.
Int. J. Hematol.
PUBLISHED: 10-09-2011
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The Bcr-Abl oncogene causes human Philadelphia chromosome-positive (Ph(+)) leukemias, including B-cell acute lymphoblastic leukemia (B-ALL) and chronic myeloid leukemia (CML) with chronic phase (CML-CP) to blast crisis (CML-BC). Previous studies have demonstrated that Src family kinases are required for the induction of B-ALL, but not for CML, which is induced by Bcr-Abl in mice. In contrast, it has been reported that Fyn is up-regulated in human CML-BC compared with CML-CP, implicating Fyn in the blast crisis transition. Here, we aimed to delineate the exact role of Fyn in the induction/progression of Ph(+) leukemias. We found that Fyn is expressed in mouse hematopoietic cells at varying stages of development, including c-kit(+)Sca-1(+)Lin(-) cells. Notably, Fyn is highly expressed in some of human lymphomas, but not in human Ph(+) leukemias including CML-BC. In mouse bone marrow transplantation models, mice transplanted with wild-type or Fyn-deficient bone marrow cells transduced with Bcr-Abl showed no differences in the development of B-ALL or CML-like diseases. Similarly, Fyn deficiency failed to impact the development of myeloid CML-BC induced by Bcr-Abl and Hes1. Elevated expression of Fyn was not found in mouse samples of Bcr-Abl-mediated CML- and CML-BC-like diseases. Thus, Fyn is not required for the pathogenesis of Bcr-Abl-mediated leukemias.
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Goods syndrome-associated pure red cell aplasia with myelodysplastic syndrome.
Intern. Med.
PUBLISHED: 09-15-2011
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We report a case of Goods syndrome-associated pure red cell aplasia (PRCA) with myelodysplastic syndrome (MDS). In this case, effector memory T (T(EM)) cells were expanded in the bone marrow. It remains uncertain whether the development of MDS was caused by the basic marrow defects or radiation therapy. However, since CD8(+) perforin(+) T(EM) cells expanded in the bone marrow, as was previously described for 3 of our patients with thymoma-associated PRCA, it is highly possible that the pathogenic mechanism of PRCA that is accompanied by thymoma is related to the expanded CD8(+) perforin(+) T(EM) cells in this MDS-complicated case.
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[Successful treatment with low-dose dasatinib in a patient with chronic eosinophilic leukemia intolerant to imatinib].
Rinsho Ketsueki
PUBLISHED: 08-09-2011
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A 77-year-old man with cough and dyspnea was admitted to hospital. Chest X-ray demonstrated reticulated shadows in the bilateral inferior lung fields and marked eosinophilia was detected in peripheral blood. Although he received steroid pulse therapy, eosinophilia became more serious and he was referred to our hospital. Bone marrow examination demonstrated a hypercellular marrow that consisted predominantly of dysplastic eosinophils with differentiation. FISH analysis of bone marrow cells demonstrated 4q12 deletion and RT-PCR analysis detected FIP1L1-PDGFRA fusion gene, leading to the diagnosis of chronic eosinophilic leukemia (CEL). Treatment with low-dose imatinib was immediately initiated; however, drug-induced systemic edema was progressive and became intolerable. Therefore, we changed imatinib to low-dose dasatinib (20 mg/day), resulting in complete molecular response of CEL after 3 months without any severe adverse effects. This is the first report on the efficacy of low-dose dasatinib for the treatment of CEL. The peak level (Cmax) of dasatinib in this patient was 55.3 nM, which exceeded the concentration of dasatinib required to inhibit cells with FIP1L1-PDGFRA by 50%. Thus, low-dose dasatinib with therapeutic drug monitoring can be a useful therapy for imatinib-intolerant CEL even in elderly patients.
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Efficacy of blood-patch pleurodesis for secondary spontaneous pneumothorax in interstitial lung disease.
Intern. Med.
PUBLISHED: 06-01-2011
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We identified the prognostic relevance of pneumothorax in interstitial lung disease (ILD) patients and evaluated the efficacy and safety of autologous blood-patch pleurodesis.
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Analysis of anatomical and functional determinants of obstructive sleep apnea.
Sleep Breath
PUBLISHED: 05-04-2011
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Craniofacial abnormalities have an important role in the occurrence of obstructive sleep apnea (OSA) and may be particularly significant in Asian patients, although obesity and functional abnormalities such as reduced lung volume and increased airway resistance also may be important. We conducted simultaneous analyses of their interrelationships to evaluate the relative contributions of obesity, craniofacial structure, pulmonary function, and airway resistance to the severity of Japanese OSA because there are little data in this area.
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Comparison of biomarkers of subclinical lung injury in obstructive sleep apnea.
Respir Med
PUBLISHED: 02-11-2011
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Obstructive sleep apnea (OSA) has both systemic and local effects partly through the increased oxidative stress caused by intermittent hypoxia and reoxygenation. However, lung-specific biomarkers in OSA have not been fully assessed in comparison with systemic biomarkers such as C-reactive protein (CRP), although results of a recent study having a small sample size indicated KL-6 as one candidate.
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Effects of the presence of hypertension on the relationship between obstructive sleep apnoea and sleepiness.
J Sleep Res
PUBLISHED: 02-09-2011
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Obstructive sleep apnoea (OSA) plays a significant role in increasing blood pressure. Significant decreases were reported in blood pressure of hypertensive OSA patients with sleepiness who underwent continuous positive airway pressure (CPAP) treatment, but not in non-sleepy hypertensive OSA patients. More recently, however, significant decreases in blood pressure in non-sleepy hypertensive OSA patients following CPAP were shown. Effects of sleepiness on hypertension in OSA patients have been investigated, but not the effects of hypertension on sleepiness in OSA patients. We investigated the relationships between hypertension and sleepiness in patients with OSA. We analysed data on 275 middle-aged male subjects from a cross-sectional epidemiological health survey. We measured blood pressure and sleep duration objectively using an actigraph for 7 days and the respiratory disturbance index (RDI) with a type 3 portable device for 2 nights, and assessed sleepiness using the Epworth Sleepiness Scale (ESS). The RDI correlated significantly with ESS scores in the 88 hypertensive subjects (r = 0.33, P = 0.0024), but not in the 187 non-hypertensive subjects (r = -0.01, P = 0.91). Short sleep duration correlated significantly with ESS scores in both groups. Both the RDI and short sleep duration were related independently to sleepiness in only hypertensive subjects. Furthermore, the RDI was related negatively significantly to sleep duration in hypertensive subjects. Although short sleep duration was related significantly to sleepiness in both groups, hypertension may be important for the sleepiness in OSA patients. Detailed mechanisms of the difference in the relationship between sleepiness and the severity of OSA with or without hypertension should be studied further.
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Molecular mechanisms that produce secondary MDS/AML by RUNX1/AML1 point mutations.
J. Cell. Biochem.
PUBLISHED: 01-27-2011
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RUNX1/AML1 point mutations have been identified in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. A heterozygous germline mutation of the RUNX1 gene causes a familial platelet disorder with a predisposition to AML. RUNX1 mutations have also been detected with high frequency in minimally differentiated AML M0 subtypes and myelodysplastic/myeloproliferative neoplasms. Here we propose a new disease category of myelodysplastic neoplasms (MDN) consisting of MDS refractory anemia with excess blasts and AML with myelodysplasia-related changes, including therapy-related cases. RUNX1 mutations have been detected in about 20% of patients with "MDN". Among the MDN cases, histories of radiation exposure, therapy-related myeloid neoplasms after successful treatment for acute promyelocytic leukemia, and leukemic transformation of myeloproliferative neoplasms have been reported to have a strong association with RUNX1 mutations. The mutations occur in a normal, a receptive, or a disease-committed hematopoietic stem cell. It is suspected that the "MDN" phenotypes are defined by the RUNX1 mutations in addition to some other abnormalities.
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Two types of C/EBP? mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models.
Blood
PUBLISHED: 09-30-2010
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Two types of mutations of a transcription factor CCAAT-enhancer binding protein ? (C/EBP?) are found in leukemic cells of 5%-14% of acute myeloid leukemia (AML) patients: N-terminal mutations expressing dominant negative p30 and C-terminal mutations in the basic leucine zipper domain. Our results showed that a mutation of C/EBP? in one allele was observed in AML after myelodysplastic syndrome, while the 2 alleles are mutated in de novo AML. Unlike an N-terminal frame-shift mutant (C/EBP?-N(m))-transduced cells, a C-terminal mutant (C/EBP?-C(m))-transduced cells alone induced AML with leukopenia in mice 4-12 months after bone marrow transplantation. Coexpression of both mutants induced AML with marked leukocytosis with shorter latencies. Interestingly, C/EBP?-C(m) collaborated with an Flt3-activating mutant Flt3-ITD in inducing AML. Moreover, C/EBP?-C(m) strongly blocked myeloid differentiation of 32Dcl3 cells, suggesting its class II mutation-like role in leukemogenesis. Although C/EBP?-C(m) failed to inhibit transcriptional activity of wild-type C/EBP?, it suppressed the synergistic effect between C/EBP? and PU.1. On the other hand, C/EBP?-N(m) inhibited C/EBP? activation in the absence of PU.1, despite low expression levels of p30 protein generated by C/EBP?-N(m). Thus, 2 types of C/EBP? mutations are implicated in leukemo-genesis, involving different and cooperating molecular mechanisms.
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Clinical and genetic features of therapy-related myeloid neoplasms after chemotherapy for acute promyelocytic leukemia.
Blood
PUBLISHED: 09-22-2010
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Acute promyelocytic leukemia (APL) is a highly curable disease with excellent complete remission and long-term survival rates. However, the development of therapy-related myeloid neoplasms (t-MN) is being reported with increasing frequency in patients successfully treated for APL. We attempted to clarify the different clinical features and hematologic findings between t-MN and relapse cases, and to identify gene alterations involved in t-MN. We compared 10 relapse and 11 t-MN cases that developed in 108 patients during their first complete remission from APL. At APL diagnosis, t-MN patients had lower white blood cell counts than did relapse patients (P = .048). Overall survival starting from chemotherapy was significantly worse in t-MN patients than in relapse patients (P = .022). The t-MN cases were characterized as CD34(+)/HLA-DR(+) and PML-RARA(-), and 4 RUNX1/AML1 mutations were detected. T-MN is easily distinguished from APL relapse by evaluating these hematologic features, and it may originate from primitive myeloid cells by chemotherapy-induced RUNX1 mutations.
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The use of non-invasive ventilation for life-threatening asthma attacks: Changes in the need for intubation.
Respirology
PUBLISHED: 04-07-2010
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Although non-invasive ventilation (NIV) has been shown to be effective in a wide variety of respiratory diseases, its role in severe asthma attacks remains uncertain. The aim of this study was to clarify the effectiveness of NIV in patients experiencing severe attacks of asthma.
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Therapeutic effect of direct hemoperfusion with a polymyxin B-immobilized fiber column in the treatment of HIV-negative severe pneumocystis pneumonia.
Respiration
PUBLISHED: 03-11-2010
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Direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) has been shown to improve oxygenation in cases of diffuse alveolar damage, but little is known about its effectiveness in treating pneumocystis pneumonia (PCP) in HIV-negative immunosuppressed patients.
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Importance of the PaCO(2) from 3 to 6 months after initiation of long-term non-invasive ventilation.
Respir Med
PUBLISHED: 01-19-2010
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The level at which arterial carbon dioxide tension (PaCO(2)) a few months after introduction of long-term non-invasive positive pressure ventilation (NPPV) is associated with a favorable prognosis remains uncertain.
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[Molecular mechanisms in myeloproliferative diseases and myelodysplastic syndromes].
Nippon Rinsho
PUBLISHED: 10-29-2009
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Little was known about the mechanisms for myeloproliferative diseases (MPD) until 2005 when an activating mutation in the JAK2 tyrosine kinase (JAK2 V617F) was identified in >95% of patients with polycythemia vera (PV), and in a significant proportion of patients with essential thormbocythemia (ET) and primary myelofibrosis (PMF). Furthermore, activating abnormalities of some tyrosine kinases were identified in MPD and related diseases, suggesting that constitutive activation of the signaling pathway is a unifying feature of these diseases. On the other hand, the molecular mechanism of myelodysplastic syndromes (MDS) is still poorly understood. Recent study revealed that two types of AML1/RUNX1 mutants function via distinct molecular mechanisms to produce mutant-specific phenotypes of MDS. The mechanisms of MPD and MDS gradually become clear.
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Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia.
Blood
PUBLISHED: 10-27-2009
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Hairy enhancer of split 1 (Hes1) is a basic helix-loop-helix transcriptional repressor that affects differentiation and often helps maintain cells in an immature state in various tissues. Here we show that retroviral expression of Hes1 immortalizes common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) in the presence of interleukin-3, conferring permanent replating capability on these cells. Whereas these cells did not develop myeloproliferative neoplasms when intravenously administered to irradiated mice, the combination of Hes1 and BCR-ABL in CMPs and GMPs caused acute leukemia resembling blast crisis of chronic myelogenous leukemia (CML), resulting in rapid death of the recipient mice. On the other hand, BCR-ABL alone caused CML-like disease when expressed in c-Kit-positive, Sca-1-positive, and lineage-negative hematopoietic stem cells (KSLs), but not committed progenitors CMPs or GMPs, as previously reported. Leukemic cells derived from Hes1 and BCR-ABL-expressing CMPs and GMPs were more immature than those derived from BCR-ABL-expressing KSLs. Intriguingly, Hes1 was highly expressed in 8 of 20 patients with CML in blast crisis, but not in the chronic phase, and dominant negative Hes1 retarded the growth of some CML cell lines expressing Hes1. These results suggest that Hes1 is a key molecule in blast crisis transition in CML.
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AML1/RUNX1 point mutation possibly promotes leukemic transformation in myeloproliferative neoplasms.
Blood
PUBLISHED: 10-22-2009
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Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by proliferation of one or more myeloid cell lineages. Some patients exhibit leukemic transformation (LT) by unknown mechanisms, and chemotherapy may increase the risk of LT. To clarify the molecular mechanisms of LT, gene alterations involved in LT from patients in the chronic phase (CP) of MPNs were identified. Among 18 patients who progressed to leukemia, AML1/RUNX1 mutations were detected in 5 patients at the LT but in none at the CP. To investigate the leukemogenic effect of AML1/RUNX1 mutants, the AML1D171N mutant was transduced into CD34(+) cells from patients in the CP of MPNs. The D171N transduction resulted in proliferation of immature myeloid cells, enhanced self-renewal capacity, and proliferation of primitive progenitors. Taken together, these results indicate that AML1/RUNX1 point mutations may have a leukemogenic potential in MPN stem cells, and they may promote leukemic transformation in MPN.
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Protein O-mannosyltransferases B and C support hyphal development and differentiation in Aspergillus nidulans.
Eukaryotic Cell
PUBLISHED: 07-31-2009
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Aspergillus nidulans possesses three pmt genes encoding protein O-d-mannosyltransferases (Pmt). Previously, we reported that PmtA, a member of the PMT2 subfamily, is involved in the proper maintenance of fungal morphology and formation of conidia (T. Oka, T. Hamaguchi, Y. Sameshima, M. Goto, and K. Furukawa, Microbiology 150:1973-1982, 2004). In the present paper, we describe the characterization of the pmtA paralogues pmtB and pmtC. PmtB and PmtC were classified as members of the PMT1 and PMT4 subfamilies, respectively. A pmtB disruptant showed wild-type (wt) colony formation at 30 degrees C but slightly repressed growth at 42 degrees C. Conidiation of the pmtB disruptant was reduced to approximately 50% of that of the wt strain; in addition, hyperbranching of hyphae indicated that PmtB is involved in polarity maintenance. A pmtA and pmtB double disruptant was viable but very slow growing, with morphological characteristics that were cumulative with respect to either single disruptant. Of the three single pmt mutants, the pmtC disruptant showed the highest growth repression; the hyphae were swollen and frequently branched, and the ability to form conidia under normal growth conditions was lost. Recovery from the aberrant hyphal structures occurred in the presence of osmotic stabilizer, implying that PmtC is responsible for the maintenance of cell wall integrity. Osmotic stabilization at 42 degrees C further enabled the pmtC disruptant to form conidiophores and conidia, but they were abnormal and much fewer than those of the wt strain. Apart from the different, abnormal phenotypes, the three pmt disruptants exhibited differences in their sensitivities to antifungal reagents, mannosylation activities, and glycoprotein profiles, indicating that PmtA, PmtB, and PmtC perform unique functions during cell growth.
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[A case of lung cancer combined with pregnancy; dramatically deteriorating condition after caesarian section].
Nihon Kokyuki Gakkai Zasshi
PUBLISHED: 07-30-2009
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A 34-year-old pregnant woman was diagnosed with pneumonia at another hospital in her 26th week of pregnancy. Antibiotics were administered, but they were not effective. She was then introduced and admitted to our hospital. Lung cancer was suspected from her chest-CT scan on admission. Caesarian section was performed on the day after admission at 33 weeks of gestation. Adenocarcinoma of the lung was diagnosed based on the results of a right-axillary lymph node biopsy performed simultaneously with the caesarian section. On the 8th day after admission, we began to administer gefitinib. We expected positive results from gefitinib, because the patient fitted the optimal profile: female, never smoker, adenocarcinoma histology. Her respiratory condition had worsened dramatically after her caesarian section, so she was given noninvasive positive pressure ventilation from the 13th day after admission. Disseminated intravascular coagulation progressed, and her chest X-ray showed bilateral extensive infiltration. Moreover, tests showed that her tumor was negative for epidermal growth factor recepter mutation, so we judged that gefitinib was not effective for her. Although her performance status was very poor, she and her family strongly desired further chemotherapy. We thus began to administer gemcitabine, but her respiratory condition deteriorated further, and she died on the 17th day after admission. Lung cancer combined with pregnancy is a very rare situation, so we report this case with some references.
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[A case of cavitating pneumococcal pneumonia developed during the treatment with etanercept for rheumatoid arthritis].
Nihon Kokyuki Gakkai Zasshi
PUBLISHED: 05-22-2009
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A 54-year-old woman who had been treated for rheumatoid arthritis (RA) with the anti-TNF-alpha drug, etanercept, was referred to our department on 27 April 2006 because of dyspnea and shock. Chest X-ray and computed tomography on admission indicated bilateral pneumonia which was proved to be caused by Streptococcus pneumoniae with positive blood culture results. The patient had recovered from multiple organ failure with intensive treatments such as NIPPV and cardiovascular support with cathecolamines, however, the left upper lobe of her lung had developed a large cavity that had been producing viable pneumococci on sputum culture for more than one month. As the development of lung necrosis and subsequent formation of a cavity is rare in patients with pneumococcal pneumonia, this case should be noted in terms of the relevance of both the fulminating pathogenecity of Streptococcus pneumoniae and the anti TNF-alpha drug treatment.
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Molecular pathways mediating MDS/AML with focus on AML1/RUNX1 point mutations.
J. Cell. Physiol.
PUBLISHED: 04-01-2009
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AML1/RUNX1 point mutations have been identified in myelodysplastic syndrome (MDS) and MDS-related acute myeloid leukemia (AML), or MDS/AML, and are distributed throughout the full length of AML1/RUNX1. Gene mutation is proposed to be one of the disease-defining genetic abnormalities of MDS/AML. Most of the mutants lose trans-activation potential, which leads to a loss of normal function indicating that AML1/RUNX1 dysfunction is one of the major pathogenic mechanisms of MDS/AML. However, N-terminal in-frame mutations (Ni-type) and C-terminal truncated mutations (Ct-type) of AML1/RUNX1 show a dominant-negative effect on the trans-activation activity, suggesting that these types of mutants may have some oncogenic potential in addition to the loss of normal function. The patients with Ni-type mutations have hypoplastic marrows with other genetic abnormalities, whereas the patients with Ct-type mutations display hyperplastic marrows without other mutations. Although biological analysis using a mouse bone marrow transplantation model transduced with Ni-type of D171N or Ct-type of S291fsX300 mutants has partially confirmed the oncogenic ability of AML1 mutants, it could not explain the mutant specific clinical features of MDS/AML. Biological analysis using human CD34(+) cells revealed that the two types exhibited distinct molecular mechanisms. Ni-type shows differentiation block without cell growth, but additional BMI-1-expression resulted in increased blastic cells. In contrast, Ct-type itself has proliferation ability. Thus, AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability.
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[An autopsy case of racemose hemangioma of bronchial arteries associated with neovascularization from the chest wall after ligation and frequent embolizations].
Nihon Kokyuki Gakkai Zasshi
PUBLISHED: 02-10-2009
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We report an autopsied 33 year old pregnant woman with racemose hemangioma of the bronchial arteries. She was first given a diagnosis of racemose hemangioma of the bronchial arteries at age 19 and underwent surgical ligation. Nevertheless, she had to be admitted to the hospital for bronchial artery embolizations every time hemoptysis recurred. In her 21st gestational week, she was admitted to our hospital because of her 9th recurrent massive hemoptysis and dyspnea. Bronchial artery embolizations were repeatedly performed under intubation to ventilate the healthy left lung separately. We succeeded in temporarily stopping the hemoptysis, but her case was complicated by bacterial pneumonia and septic shock. Her baby was born dead on day 11 and she died on day 12. The autopsy revealed abnormal convoluted and dilated arteries branching from the right intercostal and subclavian arteries and intruding into the lung parenchyma through adhesion caused by her previous thoracostomy. The connections of these abnormal arteries with pulmonary arteries and veins, which had been shown by angiography, were confirmed by autopsy. The autopsy findings suggest that temporal surgical procedures with thoracostomy in this condition can induce abnormal neovascularization via pleural adhesion.
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Impact of noninvasive ventilation (NIV) trial for various types of acute respiratory failure in the emergency department; decreased mortality and use of the ICU.
Respir Med
PUBLISHED: 02-10-2009
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Trial of noninvasive ventilation (NIV) in the emergency department (ED) for heterogeneous acute respiratory failure (ARF) has been optional and its clinical benefit unclear.
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Possible involvement of RasGRP4 in leukemogenesis.
Int. J. Hematol.
PUBLISHED: 01-25-2009
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It is now conceivable that leukemogenesis requires two types of mutations, class I and class II mutations. We previously established a mouse bone marrow-derived HF6, an IL-3-dependent cell line, that was immortalized by a class II mutation MLL/SEPT6 and can be fully transformed by class I mutations such as FLT3 mutants. To understand the molecular mechanism of leukemogenesis, particularly progression of myelodysplastic syndrome (MDS) to acute leukemia, we made cDNA libraries from the samples of patients and screened them by expression-cloning to detect class I mutations that render HF6 cells factor-independent. We identified RasGRP4, an activator of Ras, as a candidate for class I mutation from three of six patients (MDS/MPD = 1, MDS-RA = 1, MDS/AML = 2, CMMoL/AML = 1 and AML-M2 = 1). To investigate the potential roles of RasGRP4 in leukemogenesis, we tested its in vivo effect in a mouse bone marrow transplantation (BMT) model. C57BL/6J mice transplanted with RasGRP4-transduced primary bone marrow cells died of T cell leukemia, myeloid leukemia, or myeloid leukemia with T cell leukemia. To further examine if the combination of class I and class II mutations accelerated leukemic transformation, we performed a mouse BMT model in which both AML1 mutant (S291fsX300) and RasGRP4 were transduced into bone marrow cells. The double transduction led to early onset of T cell leukemia but not of AML in the transplanted mice when compared to transduction of RasGRP4 alone. Thus, we have identified RasGRP4 as a gene potentially involved in leukemogenesis and suggest that RasGRP4 cooperates with AML1 mutations in T cell leukemogenesis as a class I mutation.
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A urine biomarker for severe obstructive sleep apnoea patients: lipocalin-type prostaglandin D synthase.
Eur. Respir. J.
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Lipocalin-type prostaglandin D synthase (L-PGDS), which is responsible for the biosynthesis of prostaglandin D2, has been reported to have a close connection with cardiovascular disease and sleep regulation. This study aimed to test the hypothesis that the L-PGDS level is a useful marker to identify patients with obstructive sleep apnoea. 64 subjects were enrolled in this prospective study. Urinary concentrations of L-PGDS were measured in the morning. Measurements were made every 4 h in 25 of the 64 patients. Endothelial function was assessed by the reactive hyperaemia peripheral arterial tone index. Circadian variations in L-PGDS concentrations had a significant time-dependent fluctuation (p = 0.0002). L-PGDS was higher in the subjects with severe obstructive sleep apnoea (median 784.7 ng per mg of creatinine, n = 23) than in control subjects (262.1 ng per mg of creatinine, n = 16; p = 0.004) and in those with moderate obstructive sleep apnoea (371.7 ng per mg of creatinine, n = 25; p = 0.0008). After 2 days of continuous positive airway pressure treatment, L-PGDS concentrations in severe obstructive sleep apnoea subjects (n = 12) decreased significantly (p = 0.02) to levels present in control subjects whereas endothelial function did not change significantly. Morning urinary L-PGDS concentrations had significant correlations with the apnoea/hypopnoea index (R2 = 13.9%) and serum high-density lipoprotein cholesterol (R2 = 6.2%), but not with sleepiness. Urinary L-PGDS might be a moderately useful marker to identify patients with severe obstructive sleep apnoea.
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Impaired endothelium-dependent vasodilator response in patients with pulmonary fibrosis.
Respir Med
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Recent epidemiological evidence indicates an association between cardiovascular diseases and pulmonary fibrosis. The vascular endothelium acts to maintain vascular homeostasis through multiple mechanisms and impaired endothelial function can contribute to the development, progression and clinical expression of atherosclerosis.
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Measurement of dyspnea in patients with obstructive sleep apnea.
Sleep Breath
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Patients with obstructive sleep apnea (OSA) frequently complain of exertional dyspnea. We aimed to assess its related factors and the significance of its measurement in OSA.
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A sharp fluctuation in peripheral blood cells shortly after dasatinib administration.
Int. J. Hematol.
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Dasatinib, a tyrosine kinase inhibitor, has a reduced plasma half-life and a more extensive inhibition profile, including targeting of Src family kinases. We monitored the peripheral blood count and the serum concentration of dasatinib over time. Interestingly, we found a transient fluctuation of blood cells, which correlated with the dasatinib level. The peripheral blood count before intake of dasatinib was compared with counts measured 2 h later in blood samples from 23 patients. Total white blood cells (WBCs) increased by 2,186 ± 1,960/?L from baseline (P = 0.00002), whereas platelets decreased from a baseline of 185 ± 47 × 10(3)/?L to 164 ± 52 × 10(3)/?L (P = 0.0007). Similar phenomena were not observed in patients treated with imatinib or nilotinib. In addition, in contrast to imatinib, dasatinib strongly attenuated the expression of CD18, CD62P and CD63 by blood cells both in vivo and in vitro. These results suggest that this drug may influence the distribution of blood cells in vivo by regulating its specific adhesion molecule expression on blood cells.
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Analysis of systemic and airway inflammation in obstructive sleep apnea.
Sleep Breath
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The presence of both systemic and airway inflammation has been suggested in obstructive sleep apnea (OSA) by increased levels of inflammatory biomarkers in the circulation and respiratory specimens. We aimed to investigate the relationship between systemic and airway inflammation in OSA.
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Differences in relationships among sleep apnoea, glucose level, sleep duration and sleepiness between persons with and without type 2 diabetes.
J Sleep Res
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Obstructive sleep apnoea is common in patients with diabetes. Recently, it was reported that short sleep duration and sleepiness had deleterious effects on glucose metabolism. Thereafter, several reports showed relationships between glucose metabolism and obstructive sleep apnoea, sleep duration or sleepiness. But the interrelationships among those factors based on recent epidemiological data have not been examined. We analysed data on 275 male employees (age, 44±8years; body mass index, 23.9±3.1kg m(-2) ) who underwent a cross-sectional health examination in Japan. We measured fasting plasma glucose, sleep duration using a sleep diary and an actigraph for 7days, and respiratory disturbance index with a type 3 portable monitor for two nights. Fifty-four subjects (19.6%) had impaired glucose metabolism, with 21 having diabetes. Of those 21 (body mass index, 25.9±3.8kgm(-2) ), 17 (81.0%) had obstructive sleep apnoea (respiratory disturbance index?5). Regarding the severity of obstructive sleep apnoea, 10, four and three had mild, moderate and severe obstructive sleep apnoea, respectively. The prevalence of obstructive sleep apnoea was greater in those with than without diabetes (P=0.037). Multiple regression analyses showed that the respiratory disturbance index independently related to fasting plasma glucose only in the diabetic subjects. In patients with diabetes, after adjustment for age, waist circumference, etc. sleep fragmentation had a greater correlation with fasting plasma glucose than sleep duration, but without significance (P=0.10). Because the prevalence of obstructive sleep apnoea is extremely high in patients with diabetes, sufficient sleep duration with treatment for obstructive sleep apnoea, which ameliorates sleep fragmentation, might improve fasting plasma glucose.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.